Novel genes encoding protein kinase/protein phosphatase

ABSTRACT

Selection of clones having the kinase and/or phosphatase-like structure from clones which had been isolated and the structures thereof had been determined in the Helix Research Institute (helix clones; Japanese Patent Application No. 2000-183767) was conducted. Two novel genes were provided by carrying out homology search for all the helix clones by using the amino acid sequences of known kinases and phosphatases as queries. The genes are expected to be involved in intracellular signal transduction. The physiological functions of the inventive genes can be tested by using reporter gene assay systems capable of detecting signal transduction. The proteins of the present invention are useful as target molecules in drug discovery and in the development of new pharmaceuticals.

[0001] This is a continuation-in-part of PCT/JP00/05061, filed Jul. 28,2000, which claims priority to U.S. Provisional Application No.60/159,590, filed Oct. 18, 1999, and No. 60/183,322, filed Feb. 17,2000; and Japanese Patent Application Nos. 11-248036, filed Jul. 29,1999; 2000-118776, filed Jan. 11, 2000; 2000-183767, filed May 2, 2000;and 2000-241899, filed Jun. 9, 2000.

TECHNICAL FIELD

[0002] The present invention relates to novel human protein kinases andprotein phosphatases, as well as to genes encoding the proteins.

BACKGROUND

[0003] A variety of physiological functions of cells have to beregulated correctly and harmoniously according to need for cells todiffertiate/proliferate into normal cells, and further to exertfunctions at the tissue level. It has been well known that theregulation of the state of protein phosphorylation by proteinphosphorylation enzyme/protein kinase (hereinafter referred to as“kinase”) and protein dephosphorylation enzyme/protein phosphatase(hereinafter referred to as “phosphatase”) plays a central role in mostof such regulatory mechanisms.

[0004] Many kinase and phosphatase genes have been identified to date.It has been clarified that they form a very large protein family with awell conserved structure (Semin. Cell Biol. 5(6):367-76, 1994; Cell80(2): 225-36, 1995; Genes Cells 1(2): 147-69, 1996; Trends Biochem.Sci. 22(1):18-22, 1997; Proc Natl Acad Sci USA 96(24):13603-10, 1999).The presence of numerous types of kinases and phosphatases in cellssuggests that many types of intracellular physiological functions areprecisely regulated by kinases and phosphatases. Thus, there is apossibility that agents acting on kinase or phosphatase can moreprecisely control physiological functions as compared with known agentsrepresented by receptor agonist or receptor antagonist. Therefore, it isexpected that agents acting on kinase or phosphatase are agents, whichundesirable side effects can be much easily separated from the maineffects, and accordingly, may function as highly useful pharmaceuticals.

[0005] In order to develop such agents acting on kinase or phosphatase,first, it is required to specify the intracellular physiologicalfunction associated with each of the kinases and phosphatases, and gainsome information indicating the medical usefulness of suppressing oractivating the function. Many types of kinases and phosphatases havebeen already isolated and studied. However, there may exist manyunidentified molecules. Furthermore, with respect to kinases andphosphatases the genes of which have been isolated, it can be statedthat information on intracellular physiological functions related witheach kinase or phosphatase still are poor and has to be clarified. Theidentification of new kinase and phosphatase as well as clarification ofphysiological functions thereof is expected to make significant progressin the development of new pharmaceuticals and therapies.

SUMMARY

[0006] The object of the present invention is to provide novel humanprotein kinase and protein phosphatase proteins, genes encoding theproteins, as well as production and uses of the same.

[0007] To accomplish the object described above, the present inventorsstrenuously carried out researches as follows. First, the presentinventors tried to select clones having the kinase/phosphatase-likestructure (KP clones) from clones which had been isolated and thestructures of which had been determined in the Helix Research Institute(hereinafter referred to as “helix clones”; Japanese Patent ApplicationNo. Hei 11-248036; Japanese Patent Application No. 2000-118776; JapanesePatent Application No. 2000-183767). These helix clones are highlyexpected to have the full-length sequence, which were obtained by thecombined use of; [1] preparation of a cDNA library containing sequencesof full-length at a high rate achieved by the oligo-capping method; and[2] evaluation system for the completeness in cDNA length based on the5′-end sequence (the selection is achieved based on the evaluation usingATGpr after eliminating non-full length clones as compared with an EST).In addition, they are highly advantageous since the cDNAs are alreadyinserted into a mammalian expression vector, they can be used promptlyin experiments for the expression in cells.

[0008] The present inventors carried out homology search for all thehelix clones using the amino acid sequences of known kinases andphosphatases as queries, and selected 2 clones: “C-NT2RP3001938” and“C-OVARC1000945” (hereinafter referred to as “KP clones”). These KPclones contain full-length cDNAs encoding novel human proteins. It hasbeen known that many of known kinases and phosphatases are associatedwith a variety of signal transduction pathways in cells. Therefore,there is the possibility that the newly found KP clones having thekinase/phosphatase-like structure are also associated with some signaltransduction pathways. The potential of the KP clones as targetmolecules in drug discovery can be explored through evaluating these KPclones in various assay systems using reporter genes and deducing thephysiological functions thereof.

[0009] As described above, the present inventors found novelkinase/phosphatase proteins, and thereby accomplished the presentinvention.

[0010] Specifically, the present invention relates to novel humanprotein kinase and protein phosphatase proteins, genes encoding theproteins, and production and uses of the proteins and genes. Morespecifically, the present invention provides the following:

[0011] [1] a DNA of any one of the following (a) to (d):

[0012] (a) a DNA encoding a protein consisting of the amino acidsequence of SEQ ID NO:2 or 4,

[0013] (b) a DNA comprising the coding region of the nucleotide sequenceof SEQ ID NO:1 or 3,

[0014] (c) a DNA encoding a protein which (i) comprises the amino acidsequence of SEQ ID NO:2 or 4 in which one or more amino acids aresubstituted, deleted, inserted and/or added, and (ii) is functionallyequivalent to the protein consisting of the amino acid sequence of SEQID NO:2 or 4, and

[0015] (d) a DNA hybridizing under a stringent condition to a DNAconsisting of the nucleotide sequence of SEQ ID NO: 1 or 3, whichencodes a protein functionally equivalent to the protein consisting ofthe amino acid sequence of SEQ ID NO:2 or 4;

[0016] [2] a DNA encoding a partial peptide of a protein consisting ofthe amino acid sequence of SEQ ID NO:2 or 4;

[0017] [3] a protein or peptide encoded by the DNA of [α]or [2];

[0018] [4] a vector into which the DNA of [α]or [2] has been inserted;

[0019] [5] a host cell containing the DNA of [1] or [2], or containingthe vector of [4];

[0020] [6] a method for producing the protein or peptide of [3], whichcomprises the steps of culturing the host cell of [5], and recoveringthe expressed protein from the host cell or the culture supernatant;

[0021] [7] an antibody binding to the protein of [3];

[0022] [8] a polynucleotide containing at least 15 nucleotidescomplementary to a DNA consisting of the nucleotide sequence of SEQ IDNO: 1 or 3, or the complementary strand thereof, and

[0023] [9] a method of screening for compounds binding to the protein of[3], which comprises the steps of:

[0024] (a) contacting a test sample with the protein or a partialpeptide thereof,

[0025] (b) detecting the binding activity of the test sample with theprotein or partial peptide thereof, and

[0026] (c) selecting a compound having the activity of binding to theprotein or partial peptide thereof.

[0027] The present invention provides human-derived genes“C-NT2RP3001938” and “C-OVARC1000945” encoding novel kinase/phosphatase.The nucleotide sequence of cDNA of the human-derived gene“C-NT2RP3001938” is shown in SEQ ID NO:1, and the amino acid sequenceencoded by the cDNA is shown in SEQ ID NO:2. The nucleotide sequence ofcDNA of the human-derived gene “C-OVARC1000945” is shown in SEQ ID NO:3,and the amino acid sequence encoded by the cDNA is shown in SEQ ID NO:4.

[0028] The gene “C-NT2RP3001938” shown in SEQ ID NO:1 and“C-OVARC1000945” shown in SEQ ID NO:3 has an ORF encoding a proteinconsisting of 418 amino acids and 865 amino acids, respectively.

[0029] Hereinafter, unless otherwise stated, the above-mentioned genesof the present invention, “C-NT2RP3001938” and “C-OVARC1000945” arecollectively called “KP genes”, and proteins encoded by respective genesare collectively called “KP proteins”.

[0030] The inventive KP proteins were selected as clones having thekinase/phosphatase-like structure from the clones isolated and whosestructures had been already determined in the Helix Research Institute.The regulation of the phosphorylation state of proteins by kinase andphosphatase plays central roles in normal differentiation and/orproliferation of cells, as well as in physiological functions at thecellular level. Thus, the inventive proteins are expected to shareimportant functions in living body, and therefore, are useful as targetmolecules in drug development. In addition, the inventive KP proteinscan be used as reagents for phosphorylating or dephosphorylatingproteins.

[0031] The helix clones were prepared by a special method, and areexpected to contain cDNA of full-length chains in high probability(Japanese Patent Application No. Hei 11-248036; Japanese PatentApplication No. 2000-118776; Japanese Patent Application No.2000-183767). Furthermore, because the cDNAs are already inserted in amammalian expression vector, they can be used promptly in experimentsfor the expression in cells. Thus, information on physiologicalfunctions of the genes can be gained by successively testing thesevectors with various assay systems using reporter genes. It has beenknown that many of known kinases and phosphatases are associated with avariety of signal transduction pathways in cells, and thus, theinventive KP genes can be also associated with signal transduction.Various potential physiological functions of the inventive genes can bethoroughly examined by functional screening using reporter gene assaysystems in which known types of signal transduction can be detected.

[0032] Assay systems using reporter genes are excellent experimentalsystems which enable assessment of a variety of intracellularphysiological functions simply in a single format. Specifically, thefunctional screening is preformed by the following reporter gene assay.A vector containing the inventive KP gene is introduced into the hostcell with reporter genes having a variety of enhancer elements, and theKP gene is expressed in the cell. When the expression level of thereporter gene is altered as compared to that of the control cells inwhich no vector containing the KP gene had been introduced, it can beconcluded that the protein encoded by the KP gene acted on the enhancerelement. Useful information on physiological functions of the inventiveKP gene is expected to be provided by testing whether the inventive KPgene acts on a variety of enhancer elements or not. Large amount ofinformation on signal transduction systems acting on the elements,functional genes regulated by the enhancer elements, and so on, areknown for many enhancer elements. Thus, when a KP gene being tested isproved to act on an enhancer element, it is possible to deducephysiological functions in which the KP gene participates based on knowninformation on the enhancer element.

[0033] In the functional screening, it is also beneficial to study notonly actions of a KP gene expressed alone, but also influences of the KPgene on the action after some stimuli. More specifically, even if the KPgene alone does not exhibit any activity, there is the possibility thatthe activation of a particular element by a known type of stimulus isenhanced or suppressed by the coexpressed KP gene. Such a known type ofstimulus includes, for example, ligands of a cell surface receptor(interleukins, growth factors, TGF-β family, TNF-α family, hormones,low-molecular-weight compounds, etc.); expression of factors associatedwith intracellular signal transduction (various kinases, variousphosphatases, low-molecular-weight G protein binding protein family,Smad family, STAT family, TRAF family, cell surface receptors, etc.);stress stimuli (oxidation stress, mechanical stress, heat stress, etc.);and so on.

[0034] The assays using reporter genes can be conducted by those skilledin the art by using a variety of commercially available kits that areused conventionally. For example, Mercury™ Pathway Profiling Systemsfrom Clontech, PathDetectR Trans-Reporting System and PathDetectRCis-Reporting System from Stratagene, and such are included. The assayscan be conducted according to standard methods as described in theliterature (“Overview of Genetic Reporter Systems” In Current Protocolsin Molecular Biology, Ed. Ausubel, F. M. et al., (Wiley & Sons, NY) Unit9.6 (1995); Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press (Cold Spring Harbor, N.Y. (1989)).

[0035] When the luciferase gene is used as the reporter gene, theluciferase activity can be measured, for example, by a standard methodusing Dual-Luciferase™ Reporter Assay System from Promega or the like.

[0036] Reporter genes that can be used in the above-mentioned functionalscreening include, for example, secretory alkaline phosphatase gene,chloramphenicol acetyltransferase (CAT) gene, α-galactosidase gene, andsuch in addition to luciferase gene. Further, enhancer elements that areused in the reporter assay can be exemplified by Serum Response Element(SRE), cAMP Response Element (CRE), TPA Response Element (TRE), NFκB(Nuclear factor of κB cell)-binding element, Heat shock Response Element(HRE), Glucocorticoid Response Element (GRE), AP 1 (Activator protein 1:c-jun/c-fos complex)-binding element, NFAT (Nuclear Factor of ActivatedT-cells)-binding element, p53-binding element, interferon-γ activatedelement (Interferon Gamma Activated Sequence: GAS),Interferon-Stimulated Response Element (ISRE), E2F-binding element, STATfamily-binding element, Smad family-binding element, TCF/LEF-bindingelement, GATA family-binding element, Sterol Regulatory Element (SRE),IRF (Interferon Regulatory Factor) family-binding element, PPARγ-binding element and AhR-binding element.

[0037] 293 cell, Hela, NIH3T3, CV-1, Jurkat, vascular smooth musclecell, vascular endothelial cell, and cardiac muscle cell can beexemplified as host cells that are used in the reporter assay.

[0038] Functionally equivalent proteins to the human KP proteins (SEQ IDNOs:2 and 4) are encompassed in the present invention. Such proteinsinclude, for example, mutants, homologues, variants, and so on, of humanKP proteins. The term “functionally equivalent” herein means that theprotein of interest has a function of phosphorylating proteins and/ordephosphorylating proteins like the KP proteins. According to thefollowing procedure, it can be judged whether or not the protein ofinterest phosphorylates a protein.

[0039] A kinase protein and a substrate protein are combined together inan appropriate reaction solution. After the reaction is conduced in thepresence of ATP, the phosphorylation state of the substrate protein ismeasured to judge the phosphorylation activity. The kinase protein to beused can be purified from appropriate cell lines or extracts from tissueby commonly used biochemical methods. It is also possible to use kinaseproteins obtained by the overexpression of introduced genes encodingkinase proteins into mammalian cells (COS7, CV-1, HEK293, HeLa, Jurkat,NIH3T3, etc.), insect cells (Sf9, etc.), E. coli, yeast, and so on. Thephosphorylation state of the substrate protein can be measured in aliquid scintillation counter, autoradiography, and such, by using ATPlabeled with radioisotope, such as [γ-³²P] ATP.

[0040] Further, the phosphorylation state of the substrate protein canbe measured by ELISA (enzyme-linked immunosorbent assay), Westernblotting, etc. using phosphorylated protein specific antibodies or thelike. Such substrate proteins to be used include proteins specific toparticular kinases, as well as a variety of proteins, such as casein,histone, and myelin basic protein (MBP), which are known to bephosphorylated by non-specific kinases. Alternatively, syntheticpeptides and such containing sequences that are phosphorylated may bealso used.

[0041] Furthermore, the phosphorylation activity can be assessed bymeasuring the phosphorylation of the kinase protein per se(autophosphorylation). More specifically, the assay can be performedaccording to conventional methods described in Protein Phosphorylation:A Practical Approach. First Edition (Hardie D G. et al., OxfordUniversity Press, 1993) or others.

[0042] It can be judged whether a protein of interest dephosphorylates aprotein or not by using the following procedure.

[0043] A phosphatase protein and a pre-phosphorylated substrate proteinare combined together in an appropriate reaction solution. Then, thedecrease in the extent of phosphorylation of the substrate protein orthe amount of phosphate released from the substrate protein is measuredto assess the dephosphorylation activity. Those phosphatase proteinsprepared by the same method as those described above for the assessmentof the phosphorylation activity can be used as the phosphatase proteinin this method. The same substrate protein mentioned above for thejudgment of the phosphorylation activity can be used as the substrateprotein herein. In addition, phosphorylase, phosphorylase kinase, andsuch can be also used as substrate proteins. The pre-phosphorylation ofthe substrate protein can be achieved by using appropriate kinase suchas phosphorylase kinase, protein kinase A, tyrosine kinases includingEGF receptor and so on. The phosphorylation state of the substrateprotein can be assayed by the same method described above for theassessment of the phosphorylation activity. More specifically, the assaycan be performed according to conventional methods described in “ProteinPhosphorylation: A Practical Approach. First Edition (Hardie et al.,Oxford University Press, 1993)”, and so on.

[0044] Further, the substrate protein to be phosphorylated ordephosphorylated by a test protein can be identified by expressing acDNA expression library composed of phage vectors or the like, andassessing whether a protein expressed from each clone can be a substratefor the test protein or not. More specifically, the identification canbe carried out by referring to the method described in “EMBO J. (1997)16:1921-1933”. Alternatively, the substrate protein can be identifiedthrough the identification of proteins binding to the test protein bythe yeast two-hybrid screening or the like. More specifically, theidentification can be carried out by referring to the method describedin “EMBO J. (1997) 16:1909-1920”.

[0045] One method for preparing functionally equivalent proteins wellknown to those skilled in the art involves the introduction of mutationsinto the proteins. For example, one skilled in the art can prepareproteins functionally equivalent to the human KP protein (SEQ ID NO:2 or4) by introducing appropriate mutations into the amino acid sequence ofthe protein using the site-directed mutagenesis method (Hashimoto-Gotohet al., Gene 152:271-275, 1995; Zoller et al., Methods Enzymol.100:468-500, 1983; Kramer et al., Nucleic Acids Res. 12:9441-9456, 1984;Kramer et al., Methods. Enzymol. 154:350-367, 1987; Kunkel, Proc. Natl.Acad. Sci. USA 82:488-492, 1985; Kunkel, Methods Enzymol. 85:2763-2766,1988) and such. Mutation of amino acids may occur in nature, too. Theproteins of the present invention include proteins comprising the aminoacid sequence of human KP protein (SEQ ID NO:2 or 4) in which one ormore amino acids are mutated, so long as the resulting mutant protein isfunctionally equivalent to the protein. In such a mutant protein, thenumber of the amino acids to be mutated is usually 50 residues or less,preferably 30 residues or less, and more preferably 10 residues or less(e.g., 5 residues or less).

[0046] The amino acid residue to be mutated is preferably mutated into adifferent amino acid that allows the properties of the amino acidside-chain to be conserved. Examples of properties of amino acid sidechains include: hydrophobic amino acids (A, I, L, M, F, P, W, Y, V),hydrophilic amino acids (R, D, N, C, E, Q, G, H, K, S, T), and aminoacids comprising the following side chains: an aliphatic side-chain (G,A, V, L, I, P); a hydroxyl group containing side-chain (S, T, Y); asulfur atom containing side-chain (C, M); a carboxylic acid and amidecontaining side-chain (D, N, E, Q); a base containing side-chain (R, K,H); and an aromatic containing side-chain (H, F, Y, W) (The parentheticletters indicate the one-letter codes of amino acids).

[0047] It is well known that a protein having deletion, addition, and/orsubstitution of one or more amino acid residues in the sequence of aprotein can retain the original biological activity (Mark et al., Proc.Natl. Acad. Sci. USA 81:5662-5666, 1984; Zoller et al., Nucleic AcidsRes. 10:6487-6500, 1982; Wang et al., Science 224:1431-1433;Dalbadie-McFarland et al., Proc. Natl. Acad. Sci. USA 79:6409-6413,1982).

[0048] A protein having the amino acid sequence of human KP protein towhich one or more amino acid residues have been added, is exemplified bya fusion protein containing the human KP protein. Fusion proteins, inwhich the human KP protein is fused to other peptides or proteins, areincluded in the present invention. Fusion proteins can be made usingtechniques well known to those skilled in the art, for example, bylinking the DNA encoding the human KP protein (SEQ ID NO:2 or 4) inframe with the DNA encoding other peptides or proteins, followed byinserting the DNA into an expression vector and expressing it in a host.There is no restriction as to the peptides or proteins to be fused tothe protein of the present invention.

[0049] For instance, known peptides which may be used for the fusioninclude the FLAG peptide (Hopp et al., BioTechnology 6:1204-1210, 1988),6× His that is made up of six histidine residues, 10× His, influenzahemagglutinin (HA), human c-myc fragment, VSV-GP fragment, p18HIVfragment, T7-tag, HSV-tag, E-tag, SV40 T antigen fragment, lck tag,α-tubulin fragment, B-tag, and Protein C fragment. Also,glutathione-S-transferase (GST), influenza hemagglutinin (HA), theconstant region of immunoglobulin, β-galactosidase, maltose bindingprotein (MBP), and the like may be used as a protein to be fused withthe protein of this invention. Fusion proteins can be prepared by fusingthe DNA encoding these peptides or proteins, which are commerciallyavailable, with the DNA encoding the protein of the invention, andexpressing the fused DNA.

[0050] An alternative method for preparing functionally equivalentproteins known to those skilled in the art utilizes, for example, thehybridization technique (Sambrook et al., Molecular Cloning 2nd ed.9.47-9.58, Cold Spring Harbor Lab. Press, 1989). Generally, one skilledin the art can isolate DNAs highly homologous to the whole or part ofthe DNA sequence encoding the human KP protein (SEQ ID NO: 1 or 3), andthen isolate proteins functionally equivalent to the human KP proteinbased on those DNAs isolated. The present invention includes proteinsthat are (i) encoded by a DNA hybridizing to a DNA encoding the human KPprotein and (ii) functionally equivalent to the human KP protein. Suchproteins include, for example, homologues derived from human and otheranimals (for example, protein encoded by a DNA from mouse, rat, rabbit,cattle, etc.).

[0051] Those skilled in the art can properly select hybridizationconditions to be used for the isolation of DNAs encoding proteinsfunctionally equivalent to the human KP protein. Hybridizationconditions include low stringent conditions. Low stringent conditionsmay be, for example, 42° C. in 2× SSC and 0.1% SDS, preferably 50° C. in2× SSC and 0.1% SDS for washing after hybridization. More preferably,high stringent conditions such as 65° C. in 0.1× SSC and 0.1% SDS may bechosen. DNA with higher homology may be efficiently obtained at highertemperature under these conditions. However, several factors are thoughtto influence the stringency of hybridization, such as temperatures andsalt concentrations, and one skilled in the art can suitably selectthese factors to accomplish a similar stringency. More guidelines forthe hybridization condition are available in the art, for example, in areference by Sambrook et al., (1989, Molecular Cloning, A LaboratoryManual, Cold Spring Harbor Press, N.Y.) and in unit 2.10 of thereference by Ausubel et al. (1995, Current Protocols in MolecularBiology, John Wiley & Sons, N.Y.).

[0052] Also, in lieu of hybridization, it is also possible to isolatefunctionally equivalent proteins by a gene amplification method, such asPCR, by synthesizing sequences based on the sequence information of theDNA encoding the human KP protein (SEQ ID NO: 1 or 3) and using them asprimers.

[0053] The proteins functionally equivalent to the human KP proteinsencoded by the DNA isolated by the hybridization or gene amplificationtechniques, usually are highly homologous to the human KP proteins (SEQID NO:2 or 4) at the amino acid sequence level. The proteins of theinvention include proteins functionally equivalent to the human KPprotein and are highly homologous to the amino acid sequence of SEQ IDNO:2 or 4. “Highly homologous” means typically 65% or higher, preferably75% or higher, more preferably 85% or higher, and even more preferably95% or higher identity at the amino acid level. Homology betweenproteins can be determined according to the algorithm described in theliterature (Wilbur et al., Proc. Natl. Acad. Sci. USA 80:726-730, 1983).

[0054] The proteins of the present invention may have variations in theamino acid sequence, molecular weight, isoelectric point, presence orabsence of sugar chains, or form, depending on the cell or host used toproduce them or the purification method utilized as described below.Nevertheless, so long as the protein obtained has a function equivalentto the human KP protein, it is within the scope of the presentinvention. For example, when the inventive protein is expressed inprokaryotic cells, e.g., E. coli, a methionine residue is added at theN-terminus of the original protein. The present invention also includessuch proteins.

[0055] The proteins of the present invention can be prepared asrecombinant proteins or as naturally occurring proteins, using methodscommonly known in the art. The recombinant protein can be, for example,prepared as follows. The DNA encoding the protein of this invention(e.g., DNA having the nucleotide sequence of SEQ ID NO: 1 or 3) isinserted into an appropriate expression vector, and introduced intosuitable host cells. Subsequently, the resulting transformants, the hostcell inserted with the expression vector, are recovered, extracted andthen purified by chromatography utilizing ion exchange, reverse phase,or gel filtration, or by affinity chromatography with a column in whichthe antibodies against the protein of the present invention are fixed,or by a combination of these columns.

[0056] Alternatively, the protein of the invention can be prepared byexpressing the protein in host cells (e.g., animal cells or E. coli) asa fusion protein with glutathione S transferase protein, or as arecombinant protein with multiple histidine residues. The expressedprotein can be purified using a glutathione column or nickel column.Subsequently, if necessary, regions of the fusion protein (apart fromthe desired protein) can be digested and removed with thrombin, factorXa, etc.

[0057] The natural protein corresponding to the protein of the inventioncan be isolated by methods well known in the art, for example, bypurifying tissue or cell extracts containing a protein of the inventionwith an affinity column to which the antibody that binds to the proteinof the present invention described below is bound. The antibody may be apolyclonal antibody or monoclonal antibody.

[0058] The term “substantially pure” as used herein in reference to agiven polypeptide means that the polypeptide is substantially free fromother biological macromolecules. For example, the substantially purepolypeptide is at least 75%, 80, 85, 95, or 99% pure by dry weight.Purity can be measured by any appropriate standard method known in theart, for example, by column chromatography, polyacrylamide gelelectrophoresis, or HPLC analysis.

[0059] Accordingly, the invention includes a polypeptide having asequence shown as SEQ ID NO:2 or 4. The invention also includes apolypeptide, or fragment thereof, that differs from the correspondingsequence shown as SEQ ID NO:2 or 4. The differences are, preferably,differences or changes at a non-essential residue or a conservativesubstitution. In one embodiment, the polypeptide includes an amino acidsequence at least about 60% identical to a sequence shown as SEQ ID NO:2or 4, or a fragment thereof. Preferably, the polypeptide is at least65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more identical to SEQ IDNO:2 or 4 and has at least one phosphorylation-related function oractivity described herein, e.g., the polypeptide has a kinase orphosphatase activity. Preferred polypeptide fragments of the inventionare at least 10%, preferably at least 20%, 30%, 40%, 50%, 60%, 70%, ormore, of the length of the sequence shown as SEQ ID NO:2 or 4 and haveat least one cell differentiation-related function or activity describedherein. Or alternatively, the fragment can be merely an immunogenicfragment.

[0060] The present invention also includes partial peptides of theproteins of the present invention. The partial peptides of the presentinvention comprise at least 7 or more amino acids, preferably 8 or moreamino acids, more preferably 9 or more amino acids. The partial peptidescan be used, for example, for generating antibodies against the proteinof the present invention, screening of compounds binding to the proteinof the present invention, or screening of promoters or inhibitors forthe protein of the present invention. The partial peptides can be usedas antagonists or competitive inhibitors for the protein of thisinvention. The partial peptides of the invention can be produced bygenetic engineering, known methods of peptide synthesis, or by digestingthe protein of the invention with an appropriate peptidase. For peptidesynthesis, for example, solid phase synthesis or liquid phase synthesismay be used.

[0061] DNA encoding an inventive protein can be used for the productionof the inventive protein in vivo and in vitro as described above; it isalso applicable to, for example, gene therapy for diseases caused by theabnormality in the gene encoding the inventive protein and for diseasesthat can be treated by the inventive protein. Any type of DNA, such ascDNA synthesized from mRNA, genomic DNA or synthetic DNA, can be used solong as the DNA encodes a protein of the present invention. Also so longas they can encode a protein of the present invention, DNAs comprisingarbitrary sequences based on the degeneracy of the genetic code are alsoincluded.

[0062] As used herein, an “isolated nucleic acid” is a nucleic acid, thestructure of which is not identical to that of any naturally occurringnucleic acid or to that of any fragment of a naturally occurring genomicnucleic acid spanning more than three genes. The term therefore covers,for example, (a) a DNA which has the sequence of part of a naturallyoccurring genomic DNA molecule but is not flanked by both of the codingsequences that flank that part of the molecule in the genome of theorganism in which it naturally occurs; (b) a nucleic acid incorporatedinto a vector or into the genomic DNA of a prokaryote or eukaryote in amanner such that the resulting molecule is not identical to anynaturally occurring vector or genomic DNA; (c) a separate molecule suchas a cDNA, a genomic fragment, a fragment produced by polymerase chainreaction (PCR), or a restriction fragment; and (d) a recombinantnucleotide sequence that is part of a hybrid gene, i.e., a gene encodinga fusion protein. Specifically excluded from this definition are nucleicacids present in random, uncharacterized mixtures of different DNAmolecules, transfected cells, or cell clones, e.g., as these occur in aDNA library such as a cDNA or genomic DNA library.

[0063] Accordingly, in one aspect, the invention provides an isolated orpurified nucleic acid molecule that encodes a polypeptide describedherein or a fragment thereof. Preferably, the isolated nucleic acidmolecule includes a nucleotide sequence that is at least 60% identicalto the nucleotide sequence shown in SEQ ID NO:1 or 3. More preferably,the isolated nucleic acid molecule is at least 65%, 70%, 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, identical tothe nucleotide sequence shown in SEQ ID NO: 1 or 3. In the case of anisolated nucleic acid molecule which is longer than or equivalent inlength to the reference sequence, e.g., SEQ ID NO: 1 or 3, thecomparison is made with the full length of the reference sequence. Wherethe isolated nucleic acid molecule is shorter that the referencesequence, e.g., shorter than SEQ ID NO: 1 or 3, the comparison is madeto a segment of the reference sequence of the same length (excluding anyloop required by the homology calculation).

[0064] As used herein, “% identity” of two amino acid sequences, or oftwo nucleic acid sequences, is determined using the algorithm of Karlinand Altschul (PNAS USA 87:2264-2268, 1990), modified as in Karlin andAltschul, PNAS USA 90:5873-5877, 1993). Such an algorithm isincorporated into the NBLAST and XBLAST programs of Altschul et al. (J.Mol. Biol. 215:403-410, 1990). BLAST nucleotide searches are performedwith the NBLAST program, score=100, wordlength=12. BLAST proteinsearches are performed with the XBLAST program, score=50, wordlength=3.To obtain gapped alignment for comparison purposes GappedBLAST isutilized as described in Altschul et al (Nucleic Acids Res.25:3389-3402, 1997). When utilizing BLAST and GappedBLAST programs thedefault parameters of the respective programs (e.g., XBLAST and NBLAST)are used to obtain nucleotide sequences homologous to a nucleic acidmolecule of the invention.

[0065] The DNA of the present invention can be prepared using methodsknown in the art. For example, a cDNA library can be constructed fromthe cells expressing the protein of the present invention, andhybridization can be conducted using a part of the DNA sequence of thepresent invention (for example, SEQ ID NO: 1 or 3) as a probe. cDNAlibraries may be prepared by, for example, the method described in theliterature (Sambrook et al., Molecular Cloning, Cold Spring HarborLaboratory Press, 1989), and also, commercially available ones can beused. Alternatively, the DNA of the present invention can be obtained bypreparing the RNA from the cells expressing the protein of the presentinvention, synthesizing cDNA by reverse transcriptase, synthesizing theoligo-DNAs based on the DNA sequence of the present invention (forexample, SEQ ID NO: 1 or 3), and amplifying the cDNA encoding theprotein of the present invention by PCR using the oligonucleotides asprimers.

[0066] The nucleotide sequence of the obtained cDNA is determined tofind an open reading frame, and thereby the amino acid sequence of theprotein of the invention can be obtained. The cDNA obtained may also beused as a probe for screening a genomic library to isolate a genomicDNA.

[0067] More specifically, mRNAs may first be prepared from a cell,tissue, or organ in which the protein of the invention is expressed.Known methods can be used to isolate mRNAs; for instance, total RNA canbe prepared by guanidine ultracentrifugation (Chirgwin et al.,Biochemistry 18:5294-5299, 1979) or the AGPC method (Chomczynski et al.,Anal. Biochem. 162:156-159, 1987). mRNA may then be purified from totalRNA using mRNA Purification Kit (Pharmacia) and such; alternatively,mRNA may be directly purified by QuickPrep mRNA Purification Kit(Pharmacia).

[0068] The obtained mRNA is used to synthesize cDNA using reversetranscriptase. cDNA may be synthesized by using a kit such as the AMVReverse Transcriptase First-strand cDNA Synthesis Kit (Seikagaku Kogyo).Alternatively, cDNA may be synthesized and amplified following the5′-RACE method (Frohman et al., Proc. Natl. Acad. Sci. USA 85:8998-9002,1988; Belyavsky et al., Nucleic Acids Res. 17:2919-2932, 1989) whichuses primers described herein, the 5′-Ampli FINDER RACE Kit (Clontech),and polymerase chain reaction (PCR).

[0069] A desired DNA fragment is prepared from the PCR products andligated with a vector DNA. The recombinant vectors are used to transformE. coli and such, and a desired recombinant vector is prepared from aselected colony. The nucleotide sequence of the desired DNA is verifiedby conventional methods, such as dideoxynucleotide chain termination.

[0070] A DNA of the invention may be designed to have a sequence that isexpressed more efficiently by taking into account the frequency of codonusage in the host to be used for expression (Grantham et al., NucleicAcids Res. 9:43-74, 1981). The DNA of the present invention may bealtered by a commercially available kit or a conventional method. Forinstance, the DNA may be altered by digestion with restriction enzymes,insertion of a synthetic oligonucleotide or an appropriate DNA fragment,addition of a linker, or insertion of the initiation codon (ATG) and/orthe stop codon (TAA, TGA, or TAG).

[0071] The inventive DNA includes, specifically, a DNA comprising astretch from A at nucleotide residue 366 to C at nucleotide residue 1619from the nucleotide sequence of SEQ ID NO:1 as well as a stretch from Aat nucleotide residue 33 to A at nucleotide residue 2627 from thenucleotide sequence of SEQ ID NO:3.

[0072] The DNA of the present invention also include a DNA hybridizingto a DNA consisting of the nucleotide sequence of SEQ ID NO: 1 or 3 andencoding a protein functionally equivalent to the above-mentionedprotein of the present invention. Those skilled in the art can properlyselect the appropriate hybridization conditions, and specifically theabove-mentioned conditions can be used. Under these conditions, thehigher the temperature, the higher the homology of the obtained DNA willbe. The above-mentioned hybridizing DNA is preferably a naturallyoccurring DNA, for example, cDNA or chromosomal DNA.

[0073] The present invention also provides a vector into which a DNA ofthe present invention is inserted. The vectors of the present inventionare useful for maintaining the DNA of the present invention within hostcells or expressing the protein of the invention.

[0074] When the E. coli is used as a host cell, there is no limitationother than that the vector should have an “ori” to amplify andmass-produce the vector in E. coli (e.g., JM109, DH5α, HB101, orXL1Blue), and a marker gene for selecting the transformed E. coli (e.g.,a drug-resistance gene selected by a drug such as ampicillin,tetracycline, kanamycin, or chloramphenicol). For example, M13-seriesvectors, pUC-series vectors, pBR322, pBluescript, pCR-Script, and suchcan be used. pGEM-T, pDIRECT, pT7, and so on can also be used forsubcloning and excision of the cDNA as well as the vectors describedabove. When a vector is used to produce a protein of the presentinvention, an expression vector is especially useful. The expressionvector, for example, to be expressed in E. coli should have the abovecharacteristics to be amplified in E. coli. When E. coli, such as JM109,DH5α, HB101, or XL1 Blue, is used as the host cell, the vector shouldhave a promoter such as lacZ promoter (Ward et al., Nature 341:544-546,1989; FASEB J. 6:2422-2427, 1992), araB promoter (Better et al., Science240:1041-1043, 1988), or T7 promoter that can efficiently promote theexpression of the desired gene in E. coli. Other examples of the vectorsare pGEX-5×-1 (Pharmacia), “QlAexpress system” (Qiagen), pEGFP, and pET(for this vector, BL21, a strain expressing T7 RNA polymerase, ispreferably used as the host).

[0075] Further, the vector may contain a signal sequence for thesecretion of polypeptides. The pelB signal sequence (Lei et al., J.Bacteriol. 169:4379, 1987) can be used as a signal sequence forsecretion of proteins, when the proteins are intended to be produced inthe periplasm of E. coli. Introduction of the vector into a host cellcan be performed, for example, by the calcium chloride method orelectroporation.

[0076] In addition to the vectors for E. coli, for example, the vectorfor producing the proteins of this invention may be a mammal-derivedexpression vector (e.g., pcDNA3 (Invitrogen), pEGF-BOS (Nucleic AcidsRes. 18(17):5322, 1990), pEF, and pCDM8), an insect cell-derivedexpression vector (e.g., “Bac-to-BAC baculovairus expression system”(GibcoBRL) and pBacPAK8), a plant-derived expression vector (e.g., pMH1and pMH2), an animal virus-derived expression vector (e.g., pHSV, pMV,and pAdexLcw), a retrovirus-derived expression vector (e.g., pZIPneo),an yeast-derived expression vector (e.g., “Pichia Expression Kit”(Invitrogen), pNV11, and SP—QO1), a Bacillus subtilis-derived expressionvector (e.g., pPL608 and pKTH50).

[0077] In order to express proteins in animal cells, such as CHO, COS,and NIH3T3 cells, the vector should have a promoter necessary forexpression in such cells, e.g., SV40 promoter (Mulligan et al., Nature277:108, 1979), MMLV-LTR promoter, EF1α promoter (Mizushima et al.,Nucleic Acids Res. 18:5322, 1990), CMV promoter, etc., and morepreferably it has a marker gene for selecting transformants (forexample, a drug resistance gene selected by a drug (e.g., neomycin,G418, etc.)). Examples of vectors with these characteristics includepMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, pOP13, and so on.

[0078] The method using CHO cells deficient in nucleic acid syntheticpathways as the host, and incorporating a vector (such as PCHOI) with aDHFR gene that compensates for the deficiency and amplifying the vectorwith methotrexate (MTX) can be mentioned as an example method for stablyexpressing a gene and amplifying the copy number in cells. And as amethod for transient expression, a method transforming the COS cells,which have the gene for SV40 T antigen on the chromosome, with a vector(such as pcD) having the SV40 replication origin can be mentioned. Theorigin used for replication may be those of polyomavirus, adenovirus,bovine papilloma virus (BPV), and the like. In addition, the expressionvector may include a selection marker gene for amplification of the genecopies in host cells. Examples of such markers include, but are notlimited to, the aminoglycoside transferase (APH) gene, the thymidinekinase (TK) gene, the E. coli xanthine-guanine phosphoribosyltransferase (Ecogpt) gene, and the dihydrofolate reductase (dhfr) gene.

[0079] The DNA of the present invention can be expressed in animals by,for example, inserting a DNA of the invention into an appropriate vectorand introducing the vector into a living body by the retrovirus method,liposome method, cationic liposome method, adenovirus method, and so on.Thus, gene therapy can be conducted for diseases caused by mutations inthe KP gene of this invention. The vectors used include, but are notlimited to, adenoviral vectors (e.g., pAdexlcw) and retroviral vectors(e.g., pZIPneo). General techniques for gene manipulation, such asinsertion of the DNA of the invention into a vector, can be performedaccording to conventional methods (Molecular Cloning, 5.61-5.63). TheDNA of this invention can be administered to the living body by an exvivo method or in vivo method.

[0080] The present invention also provides a host cell into which thevector of the present invention has been introduced. The host cell intowhich the vector of the invention is introduced is not particularlylimited. E. coli and various animal cells can be used. The host cell ofthis invention can be used as, for example, a production system forproducing or expressing the protein of the invention. The productionsystem for producing a protein of the invention may be both in vitro orin vivo production system. For in vitro production, eukaryotic cells orprokaryotic cells can be used.

[0081] Useful eukaryotic host cells may be animal, plant, or fungicells. As animal cells, mammalian cells such as CHO (J. Exp. Med.108:945, 1995), COS, 3T3, myeloma, baby hamster kidney (BHK), HeLa, orVero cells, amphibian cells such as Xenopus oocytes (Valle et al.,Nature 291:340-358, 1981), or insect cells such as Sf9, Sf21, or Tn5cells can be used. CHO cells lacking DHFR gene (dhfr-CHO) (Proc. Natl.Acad. Sci. USA 77:4216-4220, 1980) or CHO K-1 (Proc. Natl. Acad. Sci.USA 60:1275, 1968) may also be used. Among the animal cells, CHO cellsare particularly preferable for high-level expression. The vector can beintroduced into the host cell by, for example, the calcium phosphatemethod, the DEAE-dextran method, cationic liposome DOTAP (BoehringerMannheim) method, electroporation, lipofection, etc.

[0082] As plant cells, for example, plant cells originating fromNicotiana tabacum are known as protein production system and may be usedas callus cultures. As fungi cells, yeast cells such as Saccharomyces,including Saccharomyces cerevisiae, or filamentous fungi such asAspergillus, including Aspergillus niger, are known.

[0083] Useful prokaryotic cells include bacterial cells, such as E.coli, for example, JM109, DH5 α, and HB101, or Bacillus subtilis.

[0084] These cells are transformed by a desired DNA, and the resultingtransformants are cultured in vitro to obtain the protein. Transformantscan be cultured using known methods. Culture medium such as DMEM, MEM,RPMI1640, or IMDM may be used for animal cells. The culture medium canbe used with or without serum supplement such as fetal calf serum (FCS).The pH of the culture medium is preferably between about 6 and 8. Cellsare typically cultured at about 30 to 40° C. for about 15 to 200 hr, andthe culture medium may be replaced, aerated, or stirred if necessary.

[0085] Animal and plant hosts may be used for in vivo production. Forexample, a desired DNA can be introduced into an animal or plant host.Encoded proteins are produced in vivo, and then are recovered. Theseanimal and plant hosts are included in host cells of the presentinvention.

[0086] Animals to be used for the production system described aboveinclude mammals and insects. Mammals such as goat, porcine, sheep,mouse, and bovine may be used (Vicki Glaser, SPECTRUM BiotechnologyApplications, 1993). Alternatively, the mammals may be transgenicanimals.

[0087] For instance, a desired DNA may be prepared as a fusion gene,fused with a gene such as goat β casein gene which encodes a proteinspecifically produced into milk. DNA fragments comprising the fusiongene are injected into goat embryos, which are then transplanted back tofemale goats. Proteins of interest can be recovered from milk producedby the transgenic goats (i.e., those born from the goats that hadreceived the embryos) or from their offspring. To increase the amount ofmilk containing the proteins produced by transgenic goats, hormones maybe appropriately administered to them (Ebert et al., Bio/Technology12:699-702, 1994).

[0088] Alternatively, insects, such as the silkworm, may be used.Baculoviruses into which the DNA encoding the protein of interest isinserted can be used to infect silkworms, and the desired protein can berecovered from their body fluid (Susumu et al., Nature 315:592-594,1985).

[0089] As plants, for example, tobacco can be used. In use of tobacco,DNA encoding the protein of interest may be inserted into a plantexpression vector, such as pMON530, which is introduced into bacteria,such as Agrobacterium tumefaciens. Then the bacteria is used to infecttobacco, such as Nicotiana tabacum, and a desired polypeptide can berecovered from their leaves (Julian et al., Eur. J. Immunol. 24:131-138,1994).

[0090] A protein of the present invention obtained as above may beisolated from inside or outside of the host cells (e.g., culture media),and purified as a substantially pure homogeneous protein. The method forprotein isolation and purification is not limited to any specificmethod; in fact, any standard method may be used. For instance, columnchromatography, filter, ultrafiltration, salt precipitation, solventprecipitation, solvent extraction, distillation, immunoprecipitation,SDS-polyacrylamide gel electrophoresis, isoelectric pointelectrophoresis, dialysis, recrystallization, and so on may beappropriately selected and combined to isolate and purify the protein.

[0091] For example, affinity chromatography, ion-exchangechromatography, hydrophobic chromatography, gel filtration, reversephase chromatography, adsorption chromatography, and such may be usedfor chromatography (Strategies for Protein Purification andCharacterization: A Laboratory Course Manual. Ed. Daniel R. Marshak etal., Cold Spring Harbor Laboratory Press, 1996). These chromatographiesmay be performed by liquid chromatography such as HPLC and FPLC. Thus,the present invention includes highly purified proteins, purified by theabove methods.

[0092] A protein of the present invention may be optionally modified orpartially deleted by treating it with an appropriate proteinmodification enzyme before or after purification. Useful proteinmodification enzymes include, but are not limited to, trypsin,chymotrypsin, lysylendopeptidase, protein kinase, glucosidase, and soon.

[0093] The present invention also provides antibodies that bind to theprotein of the invention. The antibody of the invention may take anyform, including monoclonal antibody, as well as polyclonal antibodies.Furthermore, antiserum obtained by immunizing an animal such as rabbitwith the protein of the invention, all classes of polyclonal andmonoclonal antibodies, human antibodies, and humanized antibodiesproduced by genetic recombination are included.

[0094] A protein of the invention used as the antigen to obtainantibodies may be derived from any animal species, but preferably it isderived from a mammal, such as a human, mouse, or rat, and morepreferably from human. A human-derived protein may be obtained from thenucleotide or amino acid sequences disclosed herein.

[0095] Herein, a protein used as an antigen may be a complete protein orpartial peptides thereof.

[0096] A partial peptide may be, for example, an amino (N)-terminal orcarboxy (C)-terminal fragment of the protein. Herein, an antibody isdefined as an antibody that reacts with either the full-length or afragment of the protein.

[0097] A gene encoding a protein of the invention or its fragment may beinserted into a known expression vector, which is used to transform ahost cell as described herein. The desired protein or its fragment maybe recovered from the outside or inside of the host cell by any standardmethod, and may be used as an antigen. Alternatively, cells expressingthe protein or their lysates, or a chemically synthesized protein may beused as an antigen. Short peptides are preferably used as antigens byappropriately combining them with carrier proteins such as keyholelimpet hemocyanin, bovine serum albumin, and ovalbumin.

[0098] Any mammalian animal may be immunized with the antigen, butpreferably the compatibility with parental cells used for cell fusion istaken into account. In general, animals of Rodentia, Lagomorpha, orPrimates are used.

[0099] Animals of Rodentia include, for example, mouse, rat, andhamster. Animals of Lagomorpha include, for example, rabbit. Animals ofPrimates include, for example, a monkey of Catarrhini (old world monkey)such as crab-eating monkey, rhesus monkey, sacred baboon, or chimpanzee.

[0100] Methods for immunizing animals with antigens are known in theart. For instance, intraperitoneal injection or subcutaneous injectionof antigens is used as a standard method for immunization of mammals.More specifically, antigens may be diluted and suspended in anappropriate amount with phosphate buffered saline (PBS), physiologicalsaline, etc. If desired, the antigen suspension may be mixed with anappropriate amount of a standard adjuvant, such as Freund's completeadjuvant, made into emulsion, and then administered to mammals.Preferably, it is followed by several administrations of antigen mixedwith an appropriately amount of Freund's incomplete adjuvant every 4 to21 days. An appropriate carrier may also be used for immunization. Afterimmunization as above, serum is examined for increase of the amount ofdesired antibodies by a standard method.

[0101] Polyclonal antibodies against the proteins of the presentinvention may be prepared by collecting blood from the immunized mammalexamined for the increase of desired antibodies in the serum, and byseparating serum from the blood by any conventional method. Serumcontaining the polyclonal antibodies, or if necessary, a fractioncontaining the polyclonal antibodies may be isolated from the serum tobe used as the polyclonal antibodies of the present invention. Forexample, immunoglobulin G or M can be prepared by using an affinitycolumn coupled with the protein of the invention to obtain the fractionexclusively recognizing the protein of the invention, and then,purifying the fraction by using protein A or protein G column.

[0102] To prepare monoclonal antibodies, immune cells are collected fromthe mammal immunized with the antigen and checked for the increasedlevel of desired antibodies in the serum as described above, and aresubjected to cell fusion. The immune cells used for cell fusion arepreferably obtained from spleen. The other parent cell which is fusedwith the above immune cell is preferably a mammalian myeloma cell, andmore preferably a myeloma cell that has acquired a special feature thatcan be used for selection of fusion cells by drugs.

[0103] Cell fusion of the above immune cell and myeloma cell may beperformed by any standard method, such as those described in theliterature (Galfre et al., Methods Enzymol. 73:3-46, 1981).

[0104] Hybridomas obtained by the cell fusion may be selected bycultivating them in a standard selection medium, such as HAT medium(hypoxanthine, aminopterin, and thymidine containing medium). The cellculture is typically continued in the HAT medium for several days toseveral weeks, the time being sufficient to allow all the other cells,except desired hybridoma (non-fused cells), to die. Then, the standardlimiting dilution is performed to screen and clone a hybridoma cellproducing the desired antibody.

[0105] Besides the above method, in which a nonhuman animal is immunizedwith an antigen for preparing hybridoma, human lymphocytes such as thatinfected by EB virus may be immunized with a protein, protein expressingcells, or their lysates in vitro. Then, the immunized lymphocytes arefused with human-derived myeloma cells that is capable of indefinitelydividing, such as U266, to yield a hybridoma producing a desired humanantibody, able to bind to the protein can be obtained (UnexaminedPublished Japanese Patent Application (JP-A) No. Sho 63-17688).

[0106] Subsequently, the hybridomas thus obtained are transplanted intothe abdominal cavity of a mouse from which the ascites is collected. Themonoclonal antibodies thus obtained can be purified by, for example,ammonium sulfate precipitation or by column chromatography using aprotein A or protein G column, a DEAE ion exchange column, an affinitycolumn to which the protein of the invention is coupled, and such. Theantibody of the invention can be used not only for purifying anddetecting the protein of the invention, but also as a candidate for anagonist or antagonist to the protein of the present invention. It isalso expected to use the antibody for antibody therapy of diseasesassociated with the protein of this invention. When the antibodyobtained is administered to the human body (antibody therapy), humanantibodies or humanized antibodies are preferred to reduceimmunogenicity.

[0107] For example, transgenic animals having a repertory of humanantibody genes may be immunized with a protein, protein expressingcells, or their lysates as an antigen. Antibody producing cells arecollected from the animals, and fused with myeloma cells to obtainhybridoma, from which human antibodies against the protein can beprepared (see WO92-03918, WO93-2227, WO94-02602, WO94-25585, WO96-33735,and WO96-34096).

[0108] Alternatively, an immune cell, such as an immunized lymphocyte,producing antibodies may be immortalized by an oncogene and used forpreparing monoclonal antibodies.

[0109] Monoclonal antibodies thus obtained can also be recombinantlyprepared using genetic engineering techniques (see, for example,Borrebaeck C. A. K. and Larrick J. W. Therapeutic Monoclonal Antibodies,published in the United Kingdom by MacMillan Publishers LTD (1990)). ADNA encoding an antibody may be cloned from an immune cell, such ashybridomas or immunized lymphocytes producing the antibody; insertedinto an appropriate vector; and introduced into host cells to prepare arecombinant antibody. The present invention also includes recombinantantibodies prepared as described above.

[0110] The antibody of the present invention may be a fragment of anantibody or modified antibody, so long as it binds to the protein of theinvention. For instance, the antibody fragment may be Fab, F(ab′)₂, Fv,or single chain Fv (scFv), in which Fv fragments from H and L chains areligated by an appropriate linker (Huston J. S. et al. Proc. Natl. Acad.Sci. USA 85:5879-5883, 1988). More specifically, an antibody fragmentmay be generated by treating an antibody with an enzyme such as papainor pepsin. Alternatively, a gene encoding the antibody fragment may beconstructed; inserted into an expression vector; and expressed in anappropriate host cell (see, for example, Co et al., J. Immunol.152:2968-2976, 1994; Better et al., Methods Enzymol. 178:476-496, 1989;Pluckthun et al., Methods Enzymol. 178:497-515, 1989; Lamoyi, MethodsEnzymol. 121:652-663, 1986; Rousseaux et al. Methods Enzymol.121:663-669, 1986; Bird et al., Trends Biotechnol. 9:132-137, 1991).

[0111] An antibody may be modified by conjugation with a variety ofmolecules, such as polyethylene glycol (PEG). The antibody of thepresent invention includes such modified antibodies. A modified antibodycan be obtained by chemically modifying an antibody. These modificationmethods have been already established in the field.

[0112] Alternatively, the antibody of the present invention may beobtained as a chimeric antibody, between a variable region derived fromnonhuman antibody and the constant region derived from human antibody,or as a humanized antibody, comprising the complementarity determiningregion (CDR) derived from nonhuman antibody, the frame work region (FR)derived from human antibody, and the constant region. Such antibodiescan be prepared by using known technology.

[0113] Obtained antibodies may be purified to homogeneity. Theantibodies can be separated and purified by using standard methods forprotein separation and purification. For instance, column chromatographysuch as affinity chromatography, filter, ultrafiltration, saltprecipitation, dialysis, SDS-polyacrylamide gel electrophoresis,isoelectric point electrophoresis, and so on may be appropriatelyselected and combined to isolate and purify the antibody (Antibodies: ALaboratory Manual. Ed Harlow and David Lane, Cold Spring HarborLaboratory, 1988), but methods are not limited to them. Theconcentration of the antibody obtained as described above can bedetermined by the measurement of absorbance, enzyme-linked immunosorbentassay (ELISA), or others.

[0114] Columns for affinity chromatography include protein A column andprotein G column.

[0115] For example, protein A column includes Hyper D, POROS, SepharoseF. F. (Pharmacia) and the like.

[0116] In addition to affinity chromatography, chromatographic methodsinclude, for example, ion exchange chromatography, hydrophobicchromatography, gel filtration, reverse-phase chromatography, adsorptionchromatography and others (“Strategies for Protein Purification andCharacterization: A Laboratory Course Manual” Ed Daniel R. Marshak etal., Cold Spring Harbor Laboratory Press, 1996). These chromatographicmethods can be conducted by using liquid chromatography such as HPLC andFPLC.

[0117] For example, absorbance measurement, enzyme-linked immunosorbentassay (ELISA), enzyme immunoassay (EIA), radioimmunoassay (RIA), orimmunofluorescence may be used to measure the antigen binding activityof the antibody of the invention. In ELISA, the antibody of the presentinvention is immobilized on a plate; the protein of the invention isapplied to the plate; and then a sample containing a desired antibody,such as culture supernatant of antibody producing cells or purifiedantibodies, is applied. Then, a secondary antibody that recognizes theprimary antibody and which is labeled with an enzyme such as alkalinephosphatase is applied, and the plate is incubated. After washing, anenzyme substrate, such as p-nitrophenyl phosphate, is added to theplate, and the absorbance is measured to evaluate the antigen bindingactivity of the sample. A fragment of the protein, such as a C-terminalfragment, may be used as a protein. BIAcore (Pharmacia) may be used toevaluate the activity of the antibody according to the presentinvention.

[0118] The above methods allow for the detection or measurement of theprotein of the invention, by exposing the antibody of the invention to asample assumed to contain the protein of the invention, and detecting ormeasuring the immune complex formed by the antibody and the protein.Because the method of detection or measurement of the protein accordingto the invention can specifically detect or measure a protein, themethod may be useful in a variety of experiments in which the protein isused.

[0119] The present invention also provides a polynucleotide containingat least 15 nucleotides complementary to the DNA (SEQ ID NO: 1 or 3)encoding the human KP protein or the complementary strand thereof.

[0120] Herein, the term “complementary strand” is defined as one strandof a double strand DNA composed of A:T and G:C base pair to the otherstrand. Also, “complementary” is defined as not only those completelymatching within a continuous region of at least 15 nucleotides, but alsohaving a homology of at least 70%, favorably 80% or higher, morefavorably 90% or higher, and most favorably 95% or higher within thatregion. The homology may be determined using the algorithm describedherein.

[0121] Such a nucleic acid includes probes and primers used for thedetection and amplification of DNA encoding the inventive protein;probes and primers used for the detection of expression of the DNA; andnucleotide and nucleotide derivatives (e.g., antisense oligonucleotideand ribozyme, or DNAs encoding them, etc.) used for the regulation ofexpression of the inventive protein. In addition, such a nucleic acidcan also be used for the preparation of DNA chip.

[0122] When used as primers, such nucleic acids are complementary at the3′ end, and restriction enzyme recognition sequences or tags can beadded to the 5′ end.

[0123] The antisense oligonucleotides include, for example, antisenseoligonucleotides hybridizing to any region of the nucleotide sequence ofSEQ ID NO: 1 or 3. The antisense oligonucleotide is preferably anantisense of a continuous sequence of a length of 15 nucleotides orlonger within the nucleotide sequence of SEQ ID NO:1 or 3. Morepreferably, the above continuous sequence of a length of 15 nucleotidesor longer contains the translation initiation codon.

[0124] A derivative or modified form of antisense oligonucleotide mayalso be used. The modified antisense oligonucleotides may be thosemodified with lower alkylphosphonate such as methylphosphonate andethylphosphonate; phosphorothioate; phosphoroamidate; and so on.

[0125] Herein, an antisense oligonucleotide is not restricted to thosein which all nucleotides are complementary to the correspondingnucleotides within a given region of a DNA or mRNA; so long as it canspecifically hybridize with the nucleotide sequences of SEQ ID NO: 1 or3, it may have one or more nucleotide mismatches.

[0126] A derivative of the antisense oligonucleotide of the presentinvention may act on cells producing the protein of the invention andmay bind to a DNA or mRNA encoding the protein, whereby inhibiting theexpression of the protein of the invention by inhibiting itstranscription or translation, or by promoting the degradation of mRNA,and thereby inhibiting the function of the protein of the invention.

[0127] A derivative of the antisense oligonucleotide of the presentinvention may be mixed with appropriate carriers which are inactiveagainst the derivative, and may be used as a medicine for externallyapplication such as salve or poultice.

[0128] If necessary, it may be mixed with an excipient, isotonizingagent, solubilizing agent, stabilizer, preservative, pain-killer, or thelike, and prepared as a tablet, powder, granule, capsule, liposomecapsule, injectable solution, liquid formulation, nose drops,freeze-dried agent, etc. The above may be achieved according to standardmethods.

[0129] For treating patients, a derivative of an antisenseoligonucleotide of the present invention may be, for example, directlyapplied to the affected area of a patient, or administered into bloodvessels so as to finally reach the affected area. Moreover, thederivative may be encapsulated in antisense-encapsulating materials suchas liposome, poly-L-lysine, lipid, cholesterol, lipofectin, or theirderivative in order to increase durability and/or membrane permeability.

[0130] Dose of the derivative of the antisense oligonucleotide of thepresent invention may be appropriately adjusted depending on thepatient's conditions, and a favorable amount such as 0.1 to 100 mg/kg,or more preferably 0.1 to 50 mg/kg may be administered.

[0131] As the antisense oligonucleotides of the present inventioninhibit expression of the protein of the invention, they find utility asinhibitors of the biological activity of the protein of the invention.An inhibitor of expression comprising the antisense oligonucleotide ofthe present invention is useful because it can inhibit the biologicalactivity of the protein of the invention.

[0132] The protein of the invention may be used to screen for compoundsthat bind to the protein of the present invention. Specifically, theprotein may be used in methods of screening for compounds, which methodcomprises the steps of exposing the protein of the present invention toa test sample in which a compound binding to the protein is expected tobe contained; and selecting the compound having the activity of bindingto the protein.

[0133] The proteins of the invention used for screening may berecombinant or natural proteins, or partial peptides. Alternatively,they may be expressed on the surface of cells or in the form of amembrane fraction. There is no particular restriction on the test sampleas it includes, for example, cell extract, cell culture supernatant,product of fermentation microorganism, extract from marine organism,extract from plant, purified or crude protein, peptide, non-peptidecompound, synthetic low-molecular-weight compound, natural compound,etc. The inventive protein to be contacted with a test sample can becontacted with the test sample, for example, as a purified protein, as asoluble protein, in a form of protein immobilized on carriers, as afusion protein with other proteins, in a form of protein presented oncell membrane, as a membrane fraction.

[0134] Many methods known to those skilled in the art can be used toscreen proteins capable of binding to the inventive protein. Suchscreening can be carried out, for example, by the immunoprecipitationmethod. Specifically, the method can be carried out as follows. The geneencoding a protein of this invention is expressed by inserting the geneinto a vector for foreign gene expression in pSV2neo, pcDNA I, pCD8, andsuch, and expressing the gene in animal cells, etc. Any generally usedpromoters may be employed for the expression, including the SV40 earlypromoter (Rigby In Williamson (ed.), Genetic Engineering, Vol. 3.Academic Press, London, p.83-141 (1982)), EF-1 α promoter (Kim, et al.Gene 91:217-223, 1990), CAG promoter (Niwa et al., Gene 108:193-200,1991), RSV LTR promoter (Cullen, Methods Enzymology 152:684-704, 1987),SR a promoter (Takebe et al., Mol. Cell. Biol. 8:466, 1988), CMVimmediate early promoter (Seed et al., Proc. Natl. Acad. Sci. USA84:3365-3369, 1987), SV40 late promoter (Gheysen et al., J. Mol. Appl.Genet. 1:385-394, 1982), Adenovirus late promoter (Kaufman et al., Mol.Cell. Biol. 9:946, 1989), HSV TK promoter, etc.

[0135] Transfer of a foreign gene into animal cells for its expressioncan be performed by any of the following methods, including theelectroporation method (Chu et al., Nucl. Acid Res. 15:1311-1326, 1987),the calcium phosphate method (Chen et al., Mol. Cell. Biol. 7:2745-2752,1987), the DEAE dextran method (Lopata et al., Nucl. Acids Res.12:5707-5717, 1984; Sussman et al., Mol. Cell. Biol. 4:1642-1643, 1985),the lipofectin method (Derijard, Cell. 7:1025-1037, 1994; Lamb et al.,Nature Genetics 5:22-30, 1993; Rabindran et al., Science 259:230-234,1993), etc.

[0136] The protein of this invention can be expressed as a fusionprotein having a recognition site for a monoclonal antibody byintroducing the recognition site (epitope) for the monoclonal antibody,the specificity of which has been established, into the N- or C-terminusof the protein of this invention. For this purpose, commercialepitope-antibody systems can be utilized (Igaku, Experimental Medicine13:85-90, 1995). Vectors which can express fusion proteins with theβ-galactosidase, maltose-binding protein, glutathione S-transferase,green fluorescence protein (GFP), and such, via the multi-cloning siteare commercially available.

[0137] There is also a report that a fusion protein may be prepared byintroducing only small epitope portions consisting of several to a dozenamino acid residues so as not to change the property of the protein ofthe present invention by the fusion. For example, epitopes such aspolyhistidine (His-tag), influenza hemagglutinin (HA), human c-myc,FLAG, Vesicular stomatitis virus glycoprotein (VSV-GP), T7 gene 10protein (T7-tag), human herpes simplex virus glycoprotein (HSV-tag),E-tag (epitope on the monoclonal phage), and such, and monoclonalantibodies to recognize them can be utilized as the epitope-antibodysystem for screening proteins binding to the protein of this invention(Igaku, Experimental Medicine 13:85-90, 1995).

[0138] In immunoprecipitation, immune complexes are formed by addingthese antibodies to the cell lysate prepared using suitable surfactants.The immune complex comprises a protein of this invention, a proteincomprising the binding ability with the protein, and an antibody.Immunoprecipitation can be also performed by using antibodies against aprotein of this invention, besides using antibodies against theabove-described epitopes. An antibody to a protein of this invention canbe prepared, for example, by inserting a gene encoding the protein ofthe invention into an appropriate expression vector of E. coli toexpress it in the bacterium, purifying the expressed protein, andimmunizing rabbits, mice, rats, goats, chicken, and such against thepurified protein. The antibody can be also prepared by immunizing theabove-described animals against synthetic partial peptides of theprotein of the present invention.

[0139] Immune complexes can be precipitated using, for example, ProteinA Sepharose and Protein G Sepharose when the antibody is a murine IgGantibody. In addition, if a protein of this invention is prepared as afusion protein with the epitope, such as GST, an immune complex can beformed by using a substance specifically binding to these epitopes, suchas glutathione-Sepharose 4B, in the same manner as in the use of theantibody against the protein of the present invention.

[0140] Immune precipitation, in general, may be carried out accordingto, or following the method described in the literature (Harlow, E. andLane, D.: Antibodies, pp.511-552, Cold Spring Harbor Laboratorypublications, New York, 1988).

[0141] SDS-PAGE is generally used for the analysis of immunoprecipitatedproteins. Bound proteins can be analyzed based on the molecular weightsof proteins using a gel of an appropriate concentration. In this case,although proteins bound to a protein of this invention, in general, arehardly detectable by the usual protein staining method, such asCoomassie staining and silver staining, the detection sensitivity can beimproved by culturing cells in a medium containing radioisotopes, suchas ³⁵S-methionine and ³⁵S-cysteine, to label proteins inside the cells,and detecting the labeled proteins. Once the molecular weight of theprotein is determined, the desired protein can be purified directly fromthe SDS-polyacrylamide gel and can be sequenced.

[0142] In addition, proteins binding to a protein of this invention canbe isolated using the West-western blotting method (Skolnik et al., Cell65:83-90, 1991) with the protein of this invention. Namely, cDNA isisolated from cells, tissues, and organs, in which the protein bindingto a protein of this invention is expected to be expressed (e.g., liverand kidney), and transferred into a phage vector (for example, λgt11,ZAP, and such) to prepare a cDNA library, which is then expressed onLB-agarose plates. The protein thus expressed is fixed on a filter;reacted with the labeled, purified protein of this invention; andplaques expressing a protein bound to a protein of this invention can bedetected by the label. Methods for labeling the proteins of thisinvention include methods using the binding activity of biotin andavidin; methods using antibodies specifically binding to the proteins ofthis invention, or peptides or polypeptides fused with the protein ofthis invention (e.g., GST); methods using the radioisotopes; methodsusing fluorescence; etc.

[0143] Alternatively, in another embodiment of the method for screeningof the present invention, the two-hybrid system utilizing cells may beused (Fields et al., Trends Genet. 10:286-292, 1994; Dalton et al., Cell68:597-612, 1992; “MATCHMAKER Two-Hybrid System”, “Mammalian MATCHMAKERTwo-Hybrid Assay Kit”, “MATCHMAKER One-Hybrid System (all fromClontech), “HybriZAP Two-Hybrid Vector System” (Stratagene)). In thetwo-hybrid system, an inventive protein or a partial peptide thereof isfused with the SRF DNA-binding region or GAL4 DNA-binding region, andthen is expressed in yeast cells; a cDNA library, which express proteinsin the form of fusion protein with the VP 16 or GAL4 transcriptionactivation region, is prepared from cells that are predicted to expressa protein binding to an inventive protein; the resulting cDNA library isintroduced into the above-mentioned yeast cells; and then a cDNA derivedfrom the library is isolated from a detected positive clone (when aprotein binding to the inventive protein is expressed in yeast cells,the reporter gene is activated by the binding of the two proteins, andthus positive clones are detectable). A protein encoded by the cDNA canbe prepared after the isolated cDNA is introduced and expressed in E.coli. Thus it is possible to prepare a protein binding to an inventiveprotein or the encoding gene. Reporter genes to be used in thetwo-hybrid system include, but are not limited to, for example, Ade2gene, LacZ gene, CAT gene, luciferase gene, PAI-1 (Plasminogen activatorinhibitor type1) gene in addition to HIS3 gene. The screening by thetwo-hybrid method can be conduced by using mammalian cells or others inaddition to yeast.

[0144] Compounds binding to a protein of the present invention can bescreened by affinity chromatography. For example, a protein of theinvention is immobilized on a carrier of an affinity column, and a testsample, in which a protein binding to the protein of the invention issupposed to be expressed, is applied to the column. A test sample hereinmay be, for example, cell extracts, cell lysates, etc. After loading thetest sample, the column is washed, and proteins bound to a protein ofthe invention can be prepared.

[0145] The amino acid sequence of the resulting protein is thenanalyzed. Based on the result, an oligo-DNA is synthesized and used asthe probe to screen a cDNA library. This can provide a DNA encoding theprotein.

[0146] In the present invention, a biosensor on the basis of surfaceplasmon resonance phenomenon can be used as a means to detect or assaythe bound compounds. By utilizing the biosensor on the basis of surfaceplasmon resonance phenomenon, the interaction between the inventiveprotein and a test compound can be observed as a surface plasmonresonance signal in real time using a small amount of protein withoutlabeling (e.g., BIAcore, Pharmacia). Thus the binding between theinventive protein and the test compound can be assessed by usingbiosensor of BIAcore, or the like.

[0147] In addition, methods are known in the art for isolating compoundsbinding to a protein of the invention, which are not limited only toproteins (including agonists and antagonists). Such methods include, forexample, the method of screening for a molecule binding to a protein ofthe invention by contacting a synthetic compound or natural substancebank, or a random phage peptide display library with an immobilizedprotein of the invention, and the high-throughput screening method usinga combinatorial chemistry technique (Wrighton et al., Science273:458-64, 1996; Verdine G. L., Nature 384:11-13, 1996; Hogan J. C.Jr., Nature 384:17-9, 1996).

[0148] Compounds isolated by the screening of this invention arecandidates for agents to regulate the activity of a protein of thisinvention, and thought to be applied to treatments for disorders causedby expressional and functional abnormalities, and such of the protein,and diseases which can be treated by controlling the activity of theprotein. Compounds which can be obtained by the screening method of thisinvention, the partial structure of which is modified by addition,deletion and/or substitution, are also included in the compounds bindingto the protein of this invention.

[0149] When a protein of this invention or compounds isolated by thescreening of this invention are used as drugs for humans and otheranimals, for example, mice, rats, guinea pigs, rabbits, chickens, cats,dogs, sheep, pigs, cattle, monkeys, baboons, and chimpanzees, they canbe administered by directly administering the protein or isolatedcompound itself to a patient or by administering it after formulatedaccording to known pharmaceutical methods. They can be administered, asthe occasion demands, for example, orally, as sugar-coated tablets,capsules, elixirs and microcapsules, or parenterally, in the form ofsterile solutions in water or other pharmaceutically acceptable liquids,or suspensions for injections. For example, they may be formulated byappropriately mixing with pharmaceutically acceptable carriers or media,specifically sterile water, physiological saline, plant oil, emulsifyingagents, suspending agents, surfactants, stabilizers, seasonings,excipients, vehicles, anticeptics, binders, and such, in the unit dosageform required in a generally accepted pharmaceutical procedure. Amountsof effective ingredients in these pharmaceutical preparations areadjusted so as to obtain the appropriate dose in the specified range.

[0150] Additives which can be mixed in tablets and capsules include, forexample, binders such as gelatin, corn starch, tragacanth gum and arabicgum; excipients such as crystalline cellulose; bulking agents such ascorn starch, gelatin and alginic acid; lubricants such as magnesiumstearate; sweetening agents such as sucrose, lactose or saccharine; andflavors such as peppermint, Gaultheria adenothrix oil or cherry. Whenthe dispensing unit form is a capsule, liquid carriers, such as oil, canbe further added to the above-described materials. Sterile compositionsfor injection can be prescribed using vehicles such as distilled waterfor injection according to standard pharmaceutical procedure.

[0151] Aqueous solutions for injections include, for example,physiological saline, and isotonic solutions containing: glucose andother supplements such as D-sorbitol, D-mannose, D-mannitol, sodiumchloride, and such; and suitable solubilizers, for example, alcohols,more specifically, ethanol, polyalcohols such as propylene glycol,polyethylene glycol, non-ionic surfactants such as polysorbate 80 (TM)and HCO-50 may be used together.

[0152] Oily solutions, including sesame oil and soybean oil, and benzylbenzoate and benzyl alcohol may be used together as the solubilizer.Injections may be combined with buffers such as phosphate buffer andsodium acetate buffer; soothing agents such as procaine hydrochloride;stabilizers such as benzyl alcohol, phenols and antioxidants. Injectionsthus prepared are typically filled in suitable ampules.

[0153] The administration to patients is done by methods commonly knownto those skilled in the art, such as intraarterial, intravenous, orsubcutaneous injections, as well as intranasal, bronchial,intramuscular, percutaneous, or oral administrations. One skilled in theart can suitably select the dosage according to the body-weight or ageof a patient, or the method of administration. If the compound can beencoded by DNA, the DNA may be used for gene therapy by incorporatingthe DNA into a vector for gene therapy. Dosages and administrationmethods vary depending on the body-weight, age, symptoms, and such ofpatients, but those skilled in the art can appropriately select them.

[0154] Although the specific dosage of the protein of the inventionchanges according to the subject to be treated, the target organs,symptoms, and administration methods, it is generally considered to be,for example, about 100 μg to 20 mg one day for an adult (as body-weight60 kg) in the form of injections.

[0155] Though they vary depending on the symptoms, doses of compoundsbinding to a protein of this invention or compounds regulating theactivity of such a protein may be generally in the range of about 0.1 to100 mg, preferably about 1.0 to 50 mg, and more preferably about 1.0 to20 mg per day for adults (based on the body weight 60 kg) in the case oforal administration.

[0156] Though it varies depending on the subject to be administered,target organ, symptom and method of administration, a single dose of thecompounds for the parenteral administration is thought to be preferablyadministered, for example, when it is in the form of injection,intravenously to normal adults (based on the body weight 60 kg) in therange of about 0.01 to 30 mg, preferably about 0.1 to 20 mg, and morepreferably about 0.1 to 10 mg or thereabout per day. Doses converted onthe 60 kg body weight basis or the body surface area can be similarlyadministered to other animals.

[0157] All publications and patents cited herein are incorporated byreference in their entirety

DETAILED DESCRIPTION

[0158] The invention is illustrated more specifically with reference tothe following examples, but is not to be construed as being limitedthereto.

EXAMPLE 1 Construction of a cDNA Library by the Oligo-Capping Method

[0159] The NT-2 neuron progenitor cells (Stratagene), teratocarcinomacells from human fetal testis, which can be differentiated into neuronsby the treatment with retinoic acid were cultured for two weeks afterinduction treatment by the addition of retinoic acid according to themanufacturer's instructions.

[0160] After the culture, the respective cells were collected, and mRNAwas extracted according to the method described in the literature(Sambrook et al., Molecular Cloning 2nd edition, Cold Spring harborLaboratory Press, 1989). Then, poly(A)⁺ RNA was purified by using oligodT cellulose.

[0161] Similarly, human ovary cancer tissue (OVARC1) was used to extractmRNA by the method described in the literature (Sambrook et al.,Molecular Cloning 2nd edition, Cold Spring Harbor Laboratory Press,1989). Furthermore, poly(A)⁺ RNA was purified from the mRNA usingoligo-dT cellulose.

[0162] This poly(A)⁺ RNA was used to construct a cDNA library by theoligo-capping method (Maruyama et al., Gene 138:171-174, 1994). Usingthe Oligo-cap linker (agcaucgagu cggccuuguu ggccuacugg/SEQ ID NO:5) andthe Oligo-dT primer (gcggctgaag acggcctatg tggccttttt tttttttt tt/SEQ IDNO:6), bacterial alkaline phosphatase (BAP) treatment, tobacco acidphosphatase (TAP) treatment, RNA ligation, the first strand cDNAsynthesis, and removal of RNA were performed according to the references(Suzuki et al., Protein, Nucleic acid and Enzyme, 41:197-201, 1996;Suzuki et al., Gene 200:149-156, 1997). Then, 5′- and 3′-PCR primers(agcatcgagt cggccttgtt g/SEQ ID NO:7, and gcggctgaag acggcctatg t/SEQ IDNO:8, respectively) were used for performing PCR to convert the cDNAinto double stranded cDNA, which was then digested with SfiI. Then, theDraIII-cleaved vector pUC19FL3 or pME18SFL3 (GenBank AB009864,expression vector) (NT2RP3, OVARC1) was used for cloning the cDNA in aunidirectional manner, and cDNA libraries were obtained. The nucleotidesequence of the 5′- and 3′-ends of the cDNA clones was analyzed with aDNA sequencer (ABI PRISM 377, PE Biosystems) after sequencing reactionsperformed with the DNA sequencing reagents (Dye Terminator CycleSequencing FS Ready Reaction Kit, dRhodamine Terminator Cycle SequencingFS Ready Reaction Kit, or BigDye Terminator Cycle Sequencing FS ReadyReaction Kit, PE Biosystems), according to the instructions. Theobtained data were used for a database.

[0163] Oligo-cap high full-length ratio cDNA library of NT2RP3 wasprepared by using an expression vector, pME18SFL3, which can beexpressed in eukaryotic cells. pME18SFL3 vector contains the SRαpromoter and SV40 small t intron in the upstream, as well as the SV40polyA addition signal sequence downstream of the cloning site,respectively. As the cloning site of pME18SFL3 has asymmetrical DraIIIsites, and the ends of cDNA fragments contain SfiI sites complementaryto the DraIII sites, the cloned cDNA fragments can be unidirectionallyinserted downstream of the SRα promoter. Therefore, clones containingfull-length cDNA can be expressed transiently by introducing theobtained plasmid directly into COS cells. Thus, the clones can beanalyzed very easily in terms of the proteins that are the gene productsof the clones, or in terms of the biological activities of the proteins.

EXAMPLE 2 Estimation of the Completeness at the 5′-ends of the ClonesContained in the cDNA Libraries Constructed by the Oligo-Capping Method

[0164] The full-length ratio at the 5′-end sequence of respective clonesin the human cDNA libraries constructed by the oligo-capping method wasdetermined as follows. The clones whose 5′-end sequences were consistentwith those of known human mRNA in the public database were judged to be“full-length” if they had a longer 5′-end sequence than that of theknown human mRNA; or even though the 5′-end sequence was shorter, if itcontained the translation initiation codon it was judged to have the“full-length” sequence. Clones which did not contain the translationinitiation codon were judged to be “not-full-length”. The full-lengthratio ((the number of full-length clones)/(the number of full-length andnot-full-length clones)) at the 5′-end of the cDNA clones from eachlibrary was determined by comparing with known human mRNA. As a result,the full-length ratio of the 5′-ends was 63.5%. The result indicatesthat the full-length ratio at the 5′-end sequence was extremely high inthe human cDNA clones obtained by the oligo-capping method.

EXAMPLE 3 Assessment of the Full-Length Ratio of the 5′-End of the cDNAby the ATGpr and the ESTiMateFL

[0165] The ATGpr, developed by Salamov A. A., Nishikawa T., andSwindells M. B. in the Helix Research Institute, is a program forprediction of the translation initiation codon based on thecharacteristics of the sequences in the vicinity of the ATG codon(Salamov et al., Bioinformatics 14:384-390, 1998;http://www.hri.cojp/atgpr/). The results are shown with expectations(also mentioned as ATGpr1 below) whether the ATG is a true initiationcodon (0.05-0.94). When it was not considered that the sequence was the5′-end of the cDNA or not, both of the sensitivity and specificity ofanalytical results by this program were estimated as 66%. When theprogram was applied to the 5′-end sequences of the clones from the cDNAlibrary that was obtained by the oligo-capping method having 65%full-length ratio, the sensitivity and specificity of the estimation ofthe full-length clone (clone containing the N-terminus of the ORF) wereimproved to 82 to 83% by selecting only clones having an ATGpr1 score0.6 or higher. The maximum ATGpr1 scores for 5′-end sequences ofNT2RP3001938 and OVARC1000945 were 0.32 and 0.74, respectively.

[0166] Next, the ESTiMateFL was used for the assessment of the clones.The ESTiMateFL, developed by Nishikawa and Ota in the Helix ResearchInstitute, is a method for selecting clones expected to have afull-length cDNA by comparing with the 5′-end or 3′-end sequences ofESTs in the public database.

[0167] By this method, a cDNA clone is judged to be most likely not tobe full-length if there exist any ESTs which have longer 5′-end or3′-end sequences than the clone. The method is systematized for highthroughput analysis. A clone is judged to be full-length if the clonehas a longer 5′-end sequence than the ESTs in the public databasecorresponding thereto. Even if a clone has a shorter 5′-end, the cloneis judged to be full-length if the difference in length is within 50bases, and otherwise judged not to be full-length, for convenience.Those clones whose 5′-end sequence is matching with the known mRNA,about 80% of the clones judged to be full-length by the comparison withESTs were also judged to be full-length by the assessment of the 5′-endsequence by comparing with known mRNA. Also, about 80% of the clonesjudged to be not full-length in the 5′-end sequence by comparing withESTs were also judged to be not full-length in the 5′-end sequence bycomparison with known mRNA. The precision of the estimation by comparingwith ESTs is improved with increasing numbers of ESTs to be compared.However, in case with limited numbers of ESTs, the reliability becomeslow. Thus, the method is effective in excluding clones with highprobability of being not-full-length from the cDNA clones that issynthesized by the oligo-capping method having a 5′-end sequencefull-length ratio of about 60%. In particular, the ESTiMateFL isefficiently used in estimating the full-length ratio at the 3′-endsequence of cDNA of a human unknown mRNA, a significant number of whichare deposited in the public database as EST deposits.

[0168] Results of the above assessment for the full-length ratio showedthat the clone “C-OVARC1000945” was a novel clone with a highprobability of being full-length and also which shares no sequenceidentity with any of human EST sequences at least either at the 5′-endsequence or 3′-end sequence, or both ends.

[0169] Furthermore, “C-NT2RP3001938” is also a full-length clone; thenumber of human EST sequences that shared a common sequence to each ofthese clones at the 5′-end was 20 or less (clones which do not sharesequences with certain human EST sequences at least either at the 5′-endor at 3′-end, or at both ends of the clone; excluding clones in whichthe number of human EST sequences that shared a common sequence to eachof the clones at both of the 5′- and 3-end was 1 or more and 5 or less).Accordingly, they were concluded to be novel clones.

EXAMPLE 4 Selection of Clones having a Kinase/Phosphatase-Like Sequence

[0170] Clones having a kinase/phosphatase-like sequence were selectedfrom the helix clones. All the helix clones were searched for homologyby NCBI TBLASTN2.0 by using the following 31 amino acid sequences ofknown kinases and phosphatases (also including phospholipid kinases) asqueries. Clones with a expectation value (Expect) 1.0e-05 or lower wereselected.

[0171] The query sequences used in the homology search as well as theirSEQ ID NOs and GenBank accession numbers are as follows. Query sequenceNo. SEQ ID NO: GenBank accession No. hLKB1 9 gi|3024670 hVRK1 10gi|4507903 hCDC2 11 gi|4502709 hAuroraK1 12 gb|AAC12708.1 hAuroraK2 13gi|4759178 hIKKA 14 gb|AAC51662.1 hMKK3 15 gb|AAB40653.1 hERK1 16pir|A48082 hRAF1 17 gi|4506401 hAKT 18 gi|4885061 hPIKP85 19 sp|P27986hATM 20 gi|4502267 hc-src 21 gi|4758078 hJAK1 22 ref|NP_002218.1 hFLT123 gb|AAC16449.1 hPP2A 24 gi|4506017 hMKP2 25 gb|AAC50452.1 hVHR 26gi|4758208 hPTP-SL 27 gi|4506325 hSTEP 28 sp|P54829 hPTEN 29 gi|4506249Cdc14B1 30 gb|AAD15415.1 DUSP12 31 gi|6005956 AK000449 32 gi|8923413DUS7 33 sp|Q16829 calcineurin A alpha 34 gi|6715568 PNP1 35emb|CAA56124.1 TPTE 36 gi|7019559 PPP1CC 37 gi|4506007 PP-1 gamma 38gb|AAA19823.1 PP2A 39 gi|4506017

[0172] The results of homology search were shown in Table 1. TABLE 1Search score Expectation Query Helix clone (score) value (expect)hAuroraK1 C-NT2RP3001938 55 4e-08 hAuroraK2 C-NT2RP3001938 51 5e-07hMKK3 C-NT2RP3001938 80 7e-16 hRAF1 C-NT2RP3001938 62 4e-10 PNP1C-OVARC1000945 93 5e-19

[0173] Based on the result, non-overlapping 2 clones, C-NT2RP3001938 andC-OVARC 1000945, were selected as clones having kinase/phosphatase-likestructure (KP clones). The clones encode novel human proteins, and eachof the proteins was deduced to function as a protein kinase and/or aprotein phosphatase.

EXAMPLE 5 Gene Expression Analysis by Hybridization using High DensityDNA Filter

[0174] DNA for spotting onto the nylon membranes was prepared accordingto the following procedure. E. coli was cultured in each well of a96-well plate (in a LB medium at 37° C. for 16 hours). A part of eachculture was suspended in 10 μl of sterile water in the well of a 96-wellplate. The plate was heated at 100° C. for 10 minutes. Then the sampleswere analyzed by PCR. PCR was performed in a 20 μl solution per onereaction by using TaKaRa PCR Amplification Kit (Takara) according to thesupplier's protocol. A pair of sequencing primers, ME761FW (5′tacggaagtgttacttctgc 3′/SEQ ID NO:40) and ME1250RV (5′tgtgggaggffttttctcta 3′/SEQ ID NO:41), or a pair of primers, M13M4 (5′gttttcccagtcacgac 3′/SEQ ID NO:42) and M13RV (5′ caggaaacagctatgac3′/SEQ ID NO:43) were used for the amplification of the insert cDNA inthe plasmid. PCR was performed in a thermal cycler, GeneAmp System 9600(PE Biosystems). The cycling profile consisted of pre-heating at 95° C.for 5 minutes; 10 cycles of denaturation at 95° C. for 10 seconds, andannealing/extension at 68° C. for 1 minute; 20 cycles of denaturation at98° C. for 20 seconds and annealing/extension at 60° C. for 3 minutes;and final extension at 72° C. for 10 minutes. After the PCR, 2 μl of thereaction solution was electrophoresed on a 1% agarose gel. DNA on thegel was stained with ethidium bromide to confirm the amplification ofcDNA. When cDNAs were not amplified by PCR, plasmids containing thecorresponding insert cDNAs were prepared by the alkali-extraction method(Sambrook et al., Molecular Cloning, A laboratory manual, 2nd edition,Cold Spring Harbor Laboratory Press, 1989).

[0175] DNA array was prepared by the following procedure. An Aliquot ofthe DNA solution was added to each well of a 384-well plate. DNA wasspotted onto a nylon membrane (Boehringer) by using a 384-pin tool ofBiomek 2000 Laboratory Automation System (Beckman-Coulter). Morespecifically, the 384-well plate containing the DNA was placed under the384-pin tool. The independent 384 needles of the pin tool weresimultaneously dipped into the DNA solution to fix the DNA on theneedles. The needles were gently pressed onto a nylon membrane, and theDNA fixed on the needles was spotted onto the membrane. Denaturation ofthe spotted DNA and immobilization of the DNA on the nylon membrane werecarried out according to conventional methods (Sambrook et al.,Molecular Cloning, A laboratory manual, 2nd edition, Cold Spring HarborLaboratory Press, 1989).

[0176] 1 st strand cDNA labeled with radioisotope was used as thehybridization probe. The 1 st strand cDNA was synthesized by usingThermoscript^(™) RT-PCR System (GIBCO). More specifically, the 1ststrand cDNA was synthesized by using 1.5 μg mRNAs from various humantissues (Clontech), 1 μl 50 μM Oligo(dT)20, and 50 μCi [α³³P]dATPaccording to the attached protocol. Purification of the probe wascarried out by using ProbeQuant™ G-50 micro column (Amersham-PharmaciaBiotech) according to the attached protocol. In the next step, 2 unitsof E. coli RNaseH were added to the reaction mixture. The mixture wasincubated at room temperature for 10 minutes, and then 100 μg of humanCOT-1 DNA (GIBCO) was added thereto. The mixture was incubated at 97° C.for 10 minutes, and then was allowed to stand on ice to give thehybridization probe.

[0177] Hybridization of the radioisotope-labeled probe to the DNA arraywas performed in a usual manner (Sambrook et al., Molecular Cloning, Alaboratory manual, 2nd edition, Cold Spring Harbor Laboratory Press,1989). The membrane was washed as follows: the nylon membrane was washedthree times by incubating in the Washing solution 1 (2× SSC, 1% SDS) atroom temperature (about 26° C.) for 20 minutes; then the membrane waswashed 3 times by incubating it in the Washing solution 2 (0.1× SSC, 1%SDS) at 65° C. for 20 minutes. Autoradiography was performed by using animage plate for BAS2000 (Fuji Photo Film Co., Ltd.). Specifically, thenylon membrane used for the hybridization was wrapped with a piece ofSaran Wrap, and was contacted with the light-sensitive surface of theimage plate. The membrane with the image plate was placed in an imagingcassette for radioisotope and was allowed to stand in dark for 4 hours.The radioactivity recorded on the image plate was analyzed by BAS2000(Fuji Photo Film Co., Ltd.) and was recorded as an image file of theautoradiogram by electronic conversion. The signal intensity of each DNAspot was analyzed by using Visage High Density Grid Analysis Systems(Genomic Solutions Inc.). The signal intensity was converted intonumerical data. The data were taken by duplicated measurements. Thereproducibility was assessed by comparing the signal intensities of thecorresponding spots on the duplicated DNA filters that were hybridizedto a single DNA probe. The ratio between the corresponding spots fallswithin a range of 2-folds or less in 95% of entire spots, and thecorrelation coefficient was r=0.97. Thus, the reproducibility wasassumed to be satisfactory.

[0178] The detection sensitivity in gene expression analysis wasestimated by examining increases in the signal intensity of the probeconcentration-dependent spot of the hybridization using a probecomplementary to the DNA spotted on the nylon membrane. PLACE1008092(the same DNA as that deposited in GenBank Accession No. AF107253) wasused as the DNA. The DNA array with the DNA of PLACE1008092 was preparedaccording to the above-mentioned method. The probe was prepared asfollows: mRNA was synthesized in vitro from the clone, PLACE1008092;using this mRNA as the template, radioisotope-labeled 1st strand cDNAwas synthesized in the same manner as the probe preparation methoddescribed above; and the cDNA was used as the probe. The cDNAPLACE1008092 was inserted into pBluescript SK(−), so that the 5′-end ofthe PLACE1008092 is ligated to the T7 promoter of the pBluescript SK(−)to give a recombinant plasmid for in vitro synthesis of the mRNA fromPLACE1008092. Specifically, the PLACE1008092 inserted at the DraIII siteof the pME18SFL3 was cut out by XhoI digestion. The resultingPLACE1008092 fragment was ligated to XhoI-predigested pBluescript SK(−)by using the DNA ligation kit ver.2 (Takara). The in-vitro mRNAsynthesis from PLACE1008092 inserted in pBluescript SK(−) was carriedout by using the Ampliscribe™ T7 high yield transcription kit (Epicentretechnologies). The hybridization and analysis of signal intensity ofeach DNA spot were conducted using the same methods described above.When the probe concentration was 1×10⁷ μg/ml or less, there was noincrease of signal intensity proportional to the probe concentration.Therefore it was assumed to be difficult to compare the signals with oneanother in this concentration range. Thus, spots with a intensity of 40or less were indiscriminately taken as low-level signals. Within aconcentration of the probe ranging from 1×10⁷ μg/ml to 0.1 μg/ml,signals were found to increase in a probe concentration-dependentmanner. The detection sensitivity is 1:100,000 in a ratio of mRNAexpression level in a sample.

[0179] Table 2 shows the expression of each cDNA in human normal tissues(heart, lung, pituitary gland, thymus, brain, kidney, liver and spleen).The expression levels are indicated by numerical values of 0 to 10,000.Each of the “C-NT2RP3001938” and “C-OVARC1000945” was expressed in atleast one tissue. TABLE 2 Pituitary Clone name Heart Lung gland ThymusBrain Kidney Liver Spleen GAPDH 38.210 32.670 23.820 13.580 11.23021.120 24.910 22.440 β-actin 279.280 368.870 111.100 117.500 92.880114.650 82.990 256.790 NT2RP3001938 40.274 25.723 28.062 7.496 13.89031.768 21.367 10.885 OVARC1000945 72.670 66.756 35.734 31.061 28.43944.288 57.299 34.609

EXAMPLE 6 Analysis of Disease-Associated Genes

[0180] Non-enzymic protein glycation reaction is believed to be a causeof a variety of chronic diabetic complications. Accordingly, genes ofwhich expression is elevated or decreased in a glycated protein-specificmanner are associated with diabetic complications caused by glycatedproteins. Vascular endothelial cells are affected with glycated proteinspresent in blood.

[0181] Reaction products of non-enzymic protein glycation includeamadori compound (glycated protein) as a mildly glycated protein andadvanced glycation endproduct as a heavily glycated protein. Hence,whether or not the expression of the KP genes of this invention wasvaried depending on the presence of these proteins in endothelial cellswas examined.

[0182] The mRNAs were extracted from endothelial cells that werecultured in the presence or absence of glycated protein. The mRNAs wereconverted into radiolabeled first strand cDNAs for preparing probes. Theprobes were hybridized to the above-mentioned DNA array. Signal of eachDNA spot was detected by BAS2000 and analyzed by ArrayGauge (Fuji PhotoFilm Co., Ltd.).

[0183] Advanced glycation endproduct of bovine serum albumin wasprepared as follows: bovine serum albumin (BSA; Sigma) was incubated ina phosphate buffer solution containing 50 mM glucose at 37° C. for 8weeks; and the resulting brownish BSA was dialyzed against a phosphatebuffer solution.

[0184] Human normal pulmonary arterial endothelial cells (CellApplications) were cultured in an Endothelial Cell Growth Medium (CellApplications). The culture dish (Falcon) with the cells was incubated ina CO₂ incubator (37° C., 5% CO₂, in a humid atmosphere). When the cellswere grown to be confluent in the dish, 250 μg/ml of bovine serumalbumin (sigma), glycated bovine serum albumin (Sigma) or advancedglycation endproduct of serum albumin was added thereto and the cellswere incubated for 33 hours. The mRNA was extracted from the cells byusing a FastTrack^(™) 2.0 kit (Invitrogen). The labeling ofhybridization probe was carried out by using the mRNA according to thesame procedure as described above.

[0185] Table 3 shows the expression level of each cDNA in humanpulmonary arterial endothelial cells cultured in a medium containingbovine serum albumin, glycated bovine serum albumin or advancedglycation endproduct of bovine serum albumin. The expression of“C-NT2RP3001938” was detected in the endothelial cell. TABLE 3 AdvancedGlycated Advanced glycation glycation bovine albumin endproduct ofbovine endproduct of addition/ serum albumin/ Bovine serum Glycatedbovine serum Bovine serum Bovine serum Clone name albumin bovine albuminalbumin albumin ratio albumin ratio GAPDH(Cr1) 100.81 134.21 115.16 1.331.14 βactin(Cr2) 1101.9 1092.57 997.36 0.99 0.91 NT2RP3001938 44.4242.62 38.19 0.96 0.9 

Example 7 Analysis of Ultraviolet Radiation Damage-Associated Genes

[0186] It is known that ultraviolet rays give considerably adverseinfluence on health. In recent years, the risks of tissue damage byultraviolet rays has been increased due to the destruction of the ozonelayer, and ultraviolet radiation has been recognized as a risk factorfor diseases such as skin cancers (United States EnvironmentalProtection Agency: Ozone Depletion Home Page,http://www.epa.gov/ozone/). Genes whose expression levels change withexposure of the skin epidermal cells to ultraviolet rays are consideredto be associated with skin damage caused by ultraviolet radiation.Culturing primary cultured skin fibroblast cells irradiated withultraviolet ray, it was examined whether the expression of KP genes ofthis invention varies depending on the irradiation of ultraviolet ray.First, after culturing to confluence in a culture dish, the primarycultured skin fibroblast cells (Cell Applications) were exposed to10,000 PJ/cm² of 254-nm ultraviolet light. Thereafter, messenger RNAswere extracted by using a FastTrack™ 2.0 mRNA Isolation kit (Invitrogen)from the unexposed cells and from the cells that were exposed to theultraviolet light and then cultured for 4 or 24 hours. The labeling ofthe hybridization probe was carried out by using 1.5 μg of each mRNA inthe same manner as described above. The data were obtained in triplicate(n=3). The hybridization signals were compared between the cells exposedto the ultraviolet light and the unexposed cells. The comparison waspreformed by statistical treatment with two-sample t-test. Clones withsignificant differences in the signal distribution were selected underthe condition of p<0.05. According to the analysis, the difference inthe signal values can be also detected statistically even when thesignal values are low. Accordingly, clones with signal value of 40 orlower were also assessed.

[0187] Table 4 shows the expression of each cDNA in skin-derivedfibroblast cells exposed and unexposed to ultraviolet light.

[0188] Averaged signal values (M₁, M₂) and sample variances (s₁ ², s₂ ²)were calculated for each gene in each of the cells, and then, pooledsample variances s were obtained from the sample variances of the twotypes of cells to be compared. The t values were determined according tothe following formula: t=(M₁−M₂)/s/(1/3+1/3)^(1/2). When the determinedt-value was greater than a t-value at P, probability of significancelevel, of 0.05 or 0.01 in the t-distribution table with 4 degrees offreedom, it was judged that a difference exists in the expression levelof the gene between the two types of cells at P<0.05 or P<0.01,respectively. The table also includes the information of an increase (+)or decrease (−) in the average expression level of a signal in theclones compared with that of undifferentiated cells.

[0189] The results showed that the expression level of “C-OVARC1000945”was reduced 4 hours or 24 hours after ultraviolet ray irradiation,suggesting that it is a clone associated with ultraviolet ray disorders.TABLE 4 UV_0 h UV_4 h UV_24 h t test 4 h 24 h Clone Exp. 1 Exp. 2 Exp. 3Exp. 1 Exp. 2 Exp. 3 Exp. 1 Exp. 2 Exp. 3 0/4 0/24 +/− +/− GAPDH(Cr1) 01.29 0.1 0.9 0.06 1.18 1.49 0.47 0 βactin(Cr2) 256.82 283.53 414.29388.38 117.29 329.8 189.18 190.26 157.87 * − OVARC1000945 15 14.98 13.395.71 5.62 7.78 3.1 4.11 2.76 ** ** − −

INDUSTRIAL APPLICABILITY

[0190] The present invention provides novel human protein kinase andprotein phosphatase proteins, as well as genes encoding the proteins.The regulation of the phosphorylation state of proteins by kinase and/orphosphatase plays central roles in normal differentiation and/orproliferation of cells, as well as in physiological functions at thecellular level. The novel kinases and phosphatases of the presentinvention can be assumed to be closely associated with intracellularphysiological functions, and thus, the inventive proteins are useful astarget molecules of agents in the development of pharmaceuticals.Furthermore, agents acting on the inventive proteins are expected to beeffective pharmaceuticals which can control intracellular physiologicalfunctions more precisely than agents represented by previous receptoragonists and antagonists.

1 43 1 2174 DNA Homo sapiens CDS (366)..(1619) 1 ccccgccttc tcgctgcccagccccgggga gggaggcggg gccgcgaccc cggcgcgggt 60 ggggcgaatg cgttcccagcgggtagcctg gggctggtgc agagttccaa gcccacggcc 120 ccggtcgcgg cctcgccgccctcccgcgcc ccgcgccggg agcgggccta gagcgctcgc 180 ctcgcccctc cgcgagcagggctctggcgc ccgcccctgt ccgcaccgct ggcagcctga 240 agagagtcgc tggccgtggtcgccgctagg taggatatat ctgcatcttg aaaggaagat 300 aaaacaaaag ccttctttggaatagatgga tttttgtcac tttctgtgtg aactaaagtg 360 attca atg tct ctt ttggat tgc ttc tgc act tca aga aca caa gtt gaa 410 Met Ser Leu Leu Asp CysPhe Cys Thr Ser Arg Thr Gln Val Glu 1 5 10 15 tca ctc aga cct gaa aaacag tct gaa acc agt atc cat caa tac ttg 458 Ser Leu Arg Pro Glu Lys GlnSer Glu Thr Ser Ile His Gln Tyr Leu 20 25 30 gtt gat gag cca acc ctt tcctgg tca cgt cca tcc act aga gcc agt 506 Val Asp Glu Pro Thr Leu Ser TrpSer Arg Pro Ser Thr Arg Ala Ser 35 40 45 gaa gta cta tgt tcc acc aac gtttct cac tat gag ctc caa gta gaa 554 Glu Val Leu Cys Ser Thr Asn Val SerHis Tyr Glu Leu Gln Val Glu 50 55 60 ata gga aga gga ttt gac aac ttg acttct gtc cat ctt gca cgg cat 602 Ile Gly Arg Gly Phe Asp Asn Leu Thr SerVal His Leu Ala Arg His 65 70 75 act ccc aca gga aca ctg gta act ata aaaatt aca aat ctg gaa aac 650 Thr Pro Thr Gly Thr Leu Val Thr Ile Lys IleThr Asn Leu Glu Asn 80 85 90 95 tgc aat gaa gaa cgc ctg aaa gct tta cagaaa gcc gtg att cta tcc 698 Cys Asn Glu Glu Arg Leu Lys Ala Leu Gln LysAla Val Ile Leu Ser 100 105 110 cac ttt ttc cgg cat ccc aat att aca acttat tgg aca gtt ttc act 746 His Phe Phe Arg His Pro Asn Ile Thr Thr TyrTrp Thr Val Phe Thr 115 120 125 gtt ggc agc tgg ctt tgg gtt att tct ccattt atg gcc tat ggt tca 794 Val Gly Ser Trp Leu Trp Val Ile Ser Pro PheMet Ala Tyr Gly Ser 130 135 140 gca agt caa ctc ttg agg acc tat ttt cctgaa gga atg agt gaa act 842 Ala Ser Gln Leu Leu Arg Thr Tyr Phe Pro GluGly Met Ser Glu Thr 145 150 155 tta ata aga aac att ctc ttt gga gcc gtgaga ggg ttg aac tat ctg 890 Leu Ile Arg Asn Ile Leu Phe Gly Ala Val ArgGly Leu Asn Tyr Leu 160 165 170 175 cac caa aat ggc tgt att cac agg agtatt aaa gcc agc cat atc ctc 938 His Gln Asn Gly Cys Ile His Arg Ser IleLys Ala Ser His Ile Leu 180 185 190 att tct ggt gat ggc cta gtg acc ctctct ggc ctg tcc cat ctg cat 986 Ile Ser Gly Asp Gly Leu Val Thr Leu SerGly Leu Ser His Leu His 195 200 205 agt ttg gtt aag cat gga cag agg catagg gct gtg tat gat ttc cca 1034 Ser Leu Val Lys His Gly Gln Arg His ArgAla Val Tyr Asp Phe Pro 210 215 220 cag ttc agc aca tca gtg cag ccg tggctg agt cca gaa cta ctg aga 1082 Gln Phe Ser Thr Ser Val Gln Pro Trp LeuSer Pro Glu Leu Leu Arg 225 230 235 cag gat tta cat ggg tat aat gtg aagtca gat att tac agt gtt ggg 1130 Gln Asp Leu His Gly Tyr Asn Val Lys SerAsp Ile Tyr Ser Val Gly 240 245 250 255 att aca gca tgt gaa tta gcc agtggg cag gtg cct ttc cag gac atg 1178 Ile Thr Ala Cys Glu Leu Ala Ser GlyGln Val Pro Phe Gln Asp Met 260 265 270 cat aga act cag atg ctg tta cagaaa ctg aaa ggt cct cct tat agc 1226 His Arg Thr Gln Met Leu Leu Gln LysLeu Lys Gly Pro Pro Tyr Ser 275 280 285 cca ttg gat atc agt att ttc cctcaa tca gaa tcc aga atg aaa aat 1274 Pro Leu Asp Ile Ser Ile Phe Pro GlnSer Glu Ser Arg Met Lys Asn 290 295 300 tcc cag tca ggt gta gac tct gggatt gga gaa agt gtg ctt gtc tcc 1322 Ser Gln Ser Gly Val Asp Ser Gly IleGly Glu Ser Val Leu Val Ser 305 310 315 agt gga act cac aca gta aat agtgac cga tta cac aca cca tcc tca 1370 Ser Gly Thr His Thr Val Asn Ser AspArg Leu His Thr Pro Ser Ser 320 325 330 335 aaa act ttc tct cct gcc ttcttt agc ttg gta cag ctc tgt ttg caa 1418 Lys Thr Phe Ser Pro Ala Phe PheSer Leu Val Gln Leu Cys Leu Gln 340 345 350 caa gat cct gag aaa agg ccatca gca agc agt tta ttg tcc cat gtt 1466 Gln Asp Pro Glu Lys Arg Pro SerAla Ser Ser Leu Leu Ser His Val 355 360 365 ttc ttc aaa cag atg aaa gaagaa agc cag gat tca ata ctt tca ctg 1514 Phe Phe Lys Gln Met Lys Glu GluSer Gln Asp Ser Ile Leu Ser Leu 370 375 380 ttg cct cct gct tat aac aagcca tca ata tca ttg cct cca gtg tta 1562 Leu Pro Pro Ala Tyr Asn Lys ProSer Ile Ser Leu Pro Pro Val Leu 385 390 395 cct tgg act gag cca gaa tgtgat ttt cct gat gaa aaa gac tca tac 1610 Pro Trp Thr Glu Pro Glu Cys AspPhe Pro Asp Glu Lys Asp Ser Tyr 400 405 410 415 tgg gaa ttc tagggctgccaaatcatttt atgtcctata tacttgacac 1659 Trp Glu Phe tttctccttg ctgctttttcttctgtattt ctaggtacaa ataccagaat tatacttgaa 1719 aatacagttg gtgcactggagaatctatta tttaaaacca ctctgttcaa aggggcacca 1779 gtttgtagtc cctctgtttcgcacagagta ctatgacaag gaaacatcag aattactaat 1839 ctagctagtg tcatttattctggaattttt ttctaagctg tgactaactc tttttatctc 1899 tcaatataat ttttgagccagttaattttt ttcagtattt tgctgtccct tgggaatggg 1959 ccctcagagg acagtgcttccaagtacatc ttctcccaga ttctctggcc tttttaatga 2019 gctattgtta aaccaacaggctagtttatc ttacatcaga cccttttctg gtagagggaa 2079 aatgtttgtg ctttccctttttcttctgtt aatacttatg gtaacaccta actgagcctc 2139 actcacatta aatgattcacttgaaatata tacag 2174 2 418 PRT Homo sapiens 2 Met Ser Leu Leu Asp CysPhe Cys Thr Ser Arg Thr Gln Val Glu Ser 1 5 10 15 Leu Arg Pro Glu LysGln Ser Glu Thr Ser Ile His Gln Tyr Leu Val 20 25 30 Asp Glu Pro Thr LeuSer Trp Ser Arg Pro Ser Thr Arg Ala Ser Glu 35 40 45 Val Leu Cys Ser ThrAsn Val Ser His Tyr Glu Leu Gln Val Glu Ile 50 55 60 Gly Arg Gly Phe AspAsn Leu Thr Ser Val His Leu Ala Arg His Thr 65 70 75 80 Pro Thr Gly ThrLeu Val Thr Ile Lys Ile Thr Asn Leu Glu Asn Cys 85 90 95 Asn Glu Glu ArgLeu Lys Ala Leu Gln Lys Ala Val Ile Leu Ser His 100 105 110 Phe Phe ArgHis Pro Asn Ile Thr Thr Tyr Trp Thr Val Phe Thr Val 115 120 125 Gly SerTrp Leu Trp Val Ile Ser Pro Phe Met Ala Tyr Gly Ser Ala 130 135 140 SerGln Leu Leu Arg Thr Tyr Phe Pro Glu Gly Met Ser Glu Thr Leu 145 150 155160 Ile Arg Asn Ile Leu Phe Gly Ala Val Arg Gly Leu Asn Tyr Leu His 165170 175 Gln Asn Gly Cys Ile His Arg Ser Ile Lys Ala Ser His Ile Leu Ile180 185 190 Ser Gly Asp Gly Leu Val Thr Leu Ser Gly Leu Ser His Leu HisSer 195 200 205 Leu Val Lys His Gly Gln Arg His Arg Ala Val Tyr Asp PhePro Gln 210 215 220 Phe Ser Thr Ser Val Gln Pro Trp Leu Ser Pro Glu LeuLeu Arg Gln 225 230 235 240 Asp Leu His Gly Tyr Asn Val Lys Ser Asp IleTyr Ser Val Gly Ile 245 250 255 Thr Ala Cys Glu Leu Ala Ser Gly Gln ValPro Phe Gln Asp Met His 260 265 270 Arg Thr Gln Met Leu Leu Gln Lys LeuLys Gly Pro Pro Tyr Ser Pro 275 280 285 Leu Asp Ile Ser Ile Phe Pro GlnSer Glu Ser Arg Met Lys Asn Ser 290 295 300 Gln Ser Gly Val Asp Ser GlyIle Gly Glu Ser Val Leu Val Ser Ser 305 310 315 320 Gly Thr His Thr ValAsn Ser Asp Arg Leu His Thr Pro Ser Ser Lys 325 330 335 Thr Phe Ser ProAla Phe Phe Ser Leu Val Gln Leu Cys Leu Gln Gln 340 345 350 Asp Pro GluLys Arg Pro Ser Ala Ser Ser Leu Leu Ser His Val Phe 355 360 365 Phe LysGln Met Lys Glu Glu Ser Gln Asp Ser Ile Leu Ser Leu Leu 370 375 380 ProPro Ala Tyr Asn Lys Pro Ser Ile Ser Leu Pro Pro Val Leu Pro 385 390 395400 Trp Thr Glu Pro Glu Cys Asp Phe Pro Asp Glu Lys Asp Ser Tyr Trp 405410 415 Glu Phe 3 2718 DNA Homo sapiens CDS (33)..(2627) 3 ttgaggtcacaccttcagtc cttcgagcaa at atg cct ctt cat gtt cga cgc 53 Met Pro Leu HisVal Arg Arg 1 5 agt agt gac cca gct cta att ggc ctc tcc act tct gtc agtgat agt 101 Ser Ser Asp Pro Ala Leu Ile Gly Leu Ser Thr Ser Val Ser AspSer 10 15 20 aat ttt tcc tct gaa gag cct tca agg aaa aat ccc aca cgc tggtca 149 Asn Phe Ser Ser Glu Glu Pro Ser Arg Lys Asn Pro Thr Arg Trp Ser25 30 35 aca aca gct ggc ttc ctc aag cag aac act gct ggg agt cct aaa gcc197 Thr Thr Ala Gly Phe Leu Lys Gln Asn Thr Ala Gly Ser Pro Lys Ala 4045 50 55 tgc gac agg aag aaa gat gaa aac tac aga agc ctc ccg cgg gat act245 Cys Asp Arg Lys Lys Asp Glu Asn Tyr Arg Ser Leu Pro Arg Asp Thr 6065 70 agt aac tgg tct aac caa ttt cag aga gac aat gct cgc tcg tct ctg293 Ser Asn Trp Ser Asn Gln Phe Gln Arg Asp Asn Ala Arg Ser Ser Leu 7580 85 agt gcc agt cac cca atg gtg ggc aag tgg cag gag aaa caa gaa cag341 Ser Ala Ser His Pro Met Val Gly Lys Trp Gln Glu Lys Gln Glu Gln 9095 100 gat gag gat ggg aca gaa gag gat aac agt cgt gtt gaa cct gtt gga389 Asp Glu Asp Gly Thr Glu Glu Asp Asn Ser Arg Val Glu Pro Val Gly 105110 115 cat gct gac acg ggt ttg gag cat ata ccc aac ttt tct ctg gat gat437 His Ala Asp Thr Gly Leu Glu His Ile Pro Asn Phe Ser Leu Asp Asp 120125 130 135 atg gta aag ctc gta gaa gtc ccc aac gat gga ggg cct ctg ggaatc 485 Met Val Lys Leu Val Glu Val Pro Asn Asp Gly Gly Pro Leu Gly Ile140 145 150 cat gta gtg cct ttc agt gct cga ggc ggc aga acc ctg ggg ttatta 533 His Val Val Pro Phe Ser Ala Arg Gly Gly Arg Thr Leu Gly Leu Leu155 160 165 gta aaa cga ttg gag aaa ggt ggt aaa gct gaa cat gaa aat cttttt 581 Val Lys Arg Leu Glu Lys Gly Gly Lys Ala Glu His Glu Asn Leu Phe170 175 180 cgt gag aat gat tgc att gtc agg att aat gat ggc gac ctt cgaaat 629 Arg Glu Asn Asp Cys Ile Val Arg Ile Asn Asp Gly Asp Leu Arg Asn185 190 195 aga aga ttt gaa caa gca caa cat atg ttt cgc caa gcc atg cgtaca 677 Arg Arg Phe Glu Gln Ala Gln His Met Phe Arg Gln Ala Met Arg Thr200 205 210 215 ccc atc att tgg ttc cat gtg gtt cct gca gca aat aaa gagcag tat 725 Pro Ile Ile Trp Phe His Val Val Pro Ala Ala Asn Lys Glu GlnTyr 220 225 230 gaa caa cta tcc caa agt gag aag aac aat tac tat tca agccgt ttt 773 Glu Gln Leu Ser Gln Ser Glu Lys Asn Asn Tyr Tyr Ser Ser ArgPhe 235 240 245 agc cct gac agc cag tat att gac aac agg agt gtg aac agtgca ggg 821 Ser Pro Asp Ser Gln Tyr Ile Asp Asn Arg Ser Val Asn Ser AlaGly 250 255 260 ctt cac acg gtg cag aga gca ccc cga ctg aac cac ccg cctgag cag 869 Leu His Thr Val Gln Arg Ala Pro Arg Leu Asn His Pro Pro GluGln 265 270 275 ata gac tct cac tca aga cta cct cat agc gca cac ccc tcggga aaa 917 Ile Asp Ser His Ser Arg Leu Pro His Ser Ala His Pro Ser GlyLys 280 285 290 295 cca cca tcc gct cca gcc tcg gca cct cag aat gta tttagt acg act 965 Pro Pro Ser Ala Pro Ala Ser Ala Pro Gln Asn Val Phe SerThr Thr 300 305 310 gta agc agt ggt tat aac acc aaa aaa ata ggc aag aggctt aat atc 1013 Val Ser Ser Gly Tyr Asn Thr Lys Lys Ile Gly Lys Arg LeuAsn Ile 315 320 325 cag ctt aag aaa ggt aca gaa ggt ttg gga ttc agc atcact tcc aga 1061 Gln Leu Lys Lys Gly Thr Glu Gly Leu Gly Phe Ser Ile ThrSer Arg 330 335 340 gat gta aca ata ggt ggc tca gct cca atc tat gtg aaaaac att ctc 1109 Asp Val Thr Ile Gly Gly Ser Ala Pro Ile Tyr Val Lys AsnIle Leu 345 350 355 ccc cgg ggg gcg gcc att cag gat ggc cga ctt aag gcagga gac aga 1157 Pro Arg Gly Ala Ala Ile Gln Asp Gly Arg Leu Lys Ala GlyAsp Arg 360 365 370 375 ctt ata gag gta aat gga gta gat tta gtg ggc aaatcc caa gag gaa 1205 Leu Ile Glu Val Asn Gly Val Asp Leu Val Gly Lys SerGln Glu Glu 380 385 390 gtt gtt tcg ctg ttg aga agc acc aag atg gaa ggaact gtg agc ctt 1253 Val Val Ser Leu Leu Arg Ser Thr Lys Met Glu Gly ThrVal Ser Leu 395 400 405 ctg gtc ttt cgc cag gaa gac gcc ttc cac cca agggaa ctg aat gca 1301 Leu Val Phe Arg Gln Glu Asp Ala Phe His Pro Arg GluLeu Asn Ala 410 415 420 gag cca agc cag atg cag att cca aaa gaa acg aaagca gaa gat gag 1349 Glu Pro Ser Gln Met Gln Ile Pro Lys Glu Thr Lys AlaGlu Asp Glu 425 430 435 gat att gtt ctt aca cct gat ggc acc agg gaa tttctg aca ttt gaa 1397 Asp Ile Val Leu Thr Pro Asp Gly Thr Arg Glu Phe LeuThr Phe Glu 440 445 450 455 gtc cca ctt agt gat tca gga tct gca ggc cttggt gtc agt gtc aaa 1445 Val Pro Leu Ser Asp Ser Gly Ser Ala Gly Leu GlyVal Ser Val Lys 460 465 470 ggt aac cgg tca aaa gag aac cac gca gat ttggga atc ttt gtc aag 1493 Gly Asn Arg Ser Lys Glu Asn His Ala Asp Leu GlyIle Phe Val Lys 475 480 485 tcc att att aat gga gga gca gca tct aaa gatgga agg ctt cgg gtg 1541 Ser Ile Ile Asn Gly Gly Ala Ala Ser Lys Asp GlyArg Leu Arg Val 490 495 500 aat gat caa ctg ata gca gta aat gga gaa tccctg ttg ggc aag aca 1589 Asn Asp Gln Leu Ile Ala Val Asn Gly Glu Ser LeuLeu Gly Lys Thr 505 510 515 aac caa gat gcc atg gaa acc cta aga agg tctatg tct act gaa ggc 1637 Asn Gln Asp Ala Met Glu Thr Leu Arg Arg Ser MetSer Thr Glu Gly 520 525 530 535 aat aaa cga gga atg atc cag ctt att gttgca agg aga ata agc aag 1685 Asn Lys Arg Gly Met Ile Gln Leu Ile Val AlaArg Arg Ile Ser Lys 540 545 550 tgc aat gag ctg aag tca cct ggg agc ccccct gga cct gag ctg ccc 1733 Cys Asn Glu Leu Lys Ser Pro Gly Ser Pro ProGly Pro Glu Leu Pro 555 560 565 att gaa aca gcg ttg gat gat aga gaa cgaaga att tcc cat tcc ctc 1781 Ile Glu Thr Ala Leu Asp Asp Arg Glu Arg ArgIle Ser His Ser Leu 570 575 580 tac agt ggg att gag ggg ctt gat gaa tcgccc agc aga aat gct gcc 1829 Tyr Ser Gly Ile Glu Gly Leu Asp Glu Ser ProSer Arg Asn Ala Ala 585 590 595 ctc agt agg ata atg ggt aaa tac cag ctgtcc cct aca gtg aat atg 1877 Leu Ser Arg Ile Met Gly Lys Tyr Gln Leu SerPro Thr Val Asn Met 600 605 610 615 ccc caa gat gac act gtc att ata gaagat gac agg ttg cca gtg ctt 1925 Pro Gln Asp Asp Thr Val Ile Ile Glu AspAsp Arg Leu Pro Val Leu 620 625 630 cct cca cat ctc tct gac cag tcc tcttcc agc tcc cat gat gat gtg 1973 Pro Pro His Leu Ser Asp Gln Ser Ser SerSer Ser His Asp Asp Val 635 640 645 ggg ttt gtg acg gca gat gct ggt acttgg gcc aag gct gca atc agt 2021 Gly Phe Val Thr Ala Asp Ala Gly Thr TrpAla Lys Ala Ala Ile Ser 650 655 660 gat tca gcc gac tgc tct ttg agt ccagat gtt gat cca gtt ctt gct 2069 Asp Ser Ala Asp Cys Ser Leu Ser Pro AspVal Asp Pro Val Leu Ala 665 670 675 ttt caa cga gaa gga ttt gga cgt cagact gac gag act aaa ctc aat 2117 Phe Gln Arg Glu Gly Phe Gly Arg Gln ThrAsp Glu Thr Lys Leu Asn 680 685 690 695 aca gtg gat gac cag aaa gca ggttct ccc agc aga gat gtg ggt cct 2165 Thr Val Asp Asp Gln Lys Ala Gly SerPro Ser Arg Asp Val Gly Pro 700 705 710 tcc ctg ggt ctg aag aag tca agctca ttg gag agt ctg cag acc gca 2213 Ser Leu Gly Leu Lys Lys Ser Ser SerLeu Glu Ser Leu Gln Thr Ala 715 720 725 gtt gcc gag gtg act ttg aat ggggat att cct ttc cat cgt cca cgg 2261 Val Ala Glu Val Thr Leu Asn Gly AspIle Pro Phe His Arg Pro Arg 730 735 740 ccg cgg ata atc aga ggc agg ggatgc aat gag agc ttc aga gct gcc 2309 Pro Arg Ile Ile Arg Gly Arg Gly CysAsn Glu Ser Phe Arg Ala Ala 745 750 755 atc gac aaa tct tat gat aaa cccgcg gta gat gat gat gat gaa ggc 2357 Ile Asp Lys Ser Tyr Asp Lys Pro AlaVal Asp Asp Asp Asp Glu Gly 760 765 770 775 atg gag acc ttg gaa gaa gacaca gaa gaa agt tca aga tca ggg aga 2405 Met Glu Thr Leu Glu Glu Asp ThrGlu Glu Ser Ser Arg Ser Gly Arg 780 785 790 gag tct gta tcc aca gcc agtgat cag cct tcc cac tct ctg gag aga 2453 Glu Ser Val Ser Thr Ala Ser AspGln Pro Ser His Ser Leu Glu Arg 795 800 805 caa atg aat gga aac caa gagaaa ggt gat aag act gat aga aaa aag 2501 Gln Met Asn Gly Asn Gln Glu LysGly Asp Lys Thr Asp Arg Lys Lys 810 815 820 gat aaa act gga aaa gaa aagaag aaa gat aga gat aag gag aag gat 2549 Asp Lys Thr Gly Lys Glu Lys LysLys Asp Arg Asp Lys Glu Lys Asp 825 830 835 aaa atg aaa gcc aag aag ggaatg ctg aag ggc ttg gga gac atg ttc 2597 Lys Met Lys Ala Lys Lys Gly MetLeu Lys Gly Leu Gly Asp Met Phe 840 845 850 855 agc ctt gcc aaa ctg aagccc gag aag aga tgaacaacaa agcgattcaa 2647 Ser Leu Ala Lys Leu Lys ProGlu Lys Arg 860 865 aacatgtctt gaacagcaca tattgcacag ttgttgttttttttaaacaa acaataaatt 2707 tacttttaat g 2718 4 865 PRT Homo sapiens 4Met Pro Leu His Val Arg Arg Ser Ser Asp Pro Ala Leu Ile Gly Leu 1 5 1015 Ser Thr Ser Val Ser Asp Ser Asn Phe Ser Ser Glu Glu Pro Ser Arg 20 2530 Lys Asn Pro Thr Arg Trp Ser Thr Thr Ala Gly Phe Leu Lys Gln Asn 35 4045 Thr Ala Gly Ser Pro Lys Ala Cys Asp Arg Lys Lys Asp Glu Asn Tyr 50 5560 Arg Ser Leu Pro Arg Asp Thr Ser Asn Trp Ser Asn Gln Phe Gln Arg 65 7075 80 Asp Asn Ala Arg Ser Ser Leu Ser Ala Ser His Pro Met Val Gly Lys 8590 95 Trp Gln Glu Lys Gln Glu Gln Asp Glu Asp Gly Thr Glu Glu Asp Asn100 105 110 Ser Arg Val Glu Pro Val Gly His Ala Asp Thr Gly Leu Glu HisIle 115 120 125 Pro Asn Phe Ser Leu Asp Asp Met Val Lys Leu Val Glu ValPro Asn 130 135 140 Asp Gly Gly Pro Leu Gly Ile His Val Val Pro Phe SerAla Arg Gly 145 150 155 160 Gly Arg Thr Leu Gly Leu Leu Val Lys Arg LeuGlu Lys Gly Gly Lys 165 170 175 Ala Glu His Glu Asn Leu Phe Arg Glu AsnAsp Cys Ile Val Arg Ile 180 185 190 Asn Asp Gly Asp Leu Arg Asn Arg ArgPhe Glu Gln Ala Gln His Met 195 200 205 Phe Arg Gln Ala Met Arg Thr ProIle Ile Trp Phe His Val Val Pro 210 215 220 Ala Ala Asn Lys Glu Gln TyrGlu Gln Leu Ser Gln Ser Glu Lys Asn 225 230 235 240 Asn Tyr Tyr Ser SerArg Phe Ser Pro Asp Ser Gln Tyr Ile Asp Asn 245 250 255 Arg Ser Val AsnSer Ala Gly Leu His Thr Val Gln Arg Ala Pro Arg 260 265 270 Leu Asn HisPro Pro Glu Gln Ile Asp Ser His Ser Arg Leu Pro His 275 280 285 Ser AlaHis Pro Ser Gly Lys Pro Pro Ser Ala Pro Ala Ser Ala Pro 290 295 300 GlnAsn Val Phe Ser Thr Thr Val Ser Ser Gly Tyr Asn Thr Lys Lys 305 310 315320 Ile Gly Lys Arg Leu Asn Ile Gln Leu Lys Lys Gly Thr Glu Gly Leu 325330 335 Gly Phe Ser Ile Thr Ser Arg Asp Val Thr Ile Gly Gly Ser Ala Pro340 345 350 Ile Tyr Val Lys Asn Ile Leu Pro Arg Gly Ala Ala Ile Gln AspGly 355 360 365 Arg Leu Lys Ala Gly Asp Arg Leu Ile Glu Val Asn Gly ValAsp Leu 370 375 380 Val Gly Lys Ser Gln Glu Glu Val Val Ser Leu Leu ArgSer Thr Lys 385 390 395 400 Met Glu Gly Thr Val Ser Leu Leu Val Phe ArgGln Glu Asp Ala Phe 405 410 415 His Pro Arg Glu Leu Asn Ala Glu Pro SerGln Met Gln Ile Pro Lys 420 425 430 Glu Thr Lys Ala Glu Asp Glu Asp IleVal Leu Thr Pro Asp Gly Thr 435 440 445 Arg Glu Phe Leu Thr Phe Glu ValPro Leu Ser Asp Ser Gly Ser Ala 450 455 460 Gly Leu Gly Val Ser Val LysGly Asn Arg Ser Lys Glu Asn His Ala 465 470 475 480 Asp Leu Gly Ile PheVal Lys Ser Ile Ile Asn Gly Gly Ala Ala Ser 485 490 495 Lys Asp Gly ArgLeu Arg Val Asn Asp Gln Leu Ile Ala Val Asn Gly 500 505 510 Glu Ser LeuLeu Gly Lys Thr Asn Gln Asp Ala Met Glu Thr Leu Arg 515 520 525 Arg SerMet Ser Thr Glu Gly Asn Lys Arg Gly Met Ile Gln Leu Ile 530 535 540 ValAla Arg Arg Ile Ser Lys Cys Asn Glu Leu Lys Ser Pro Gly Ser 545 550 555560 Pro Pro Gly Pro Glu Leu Pro Ile Glu Thr Ala Leu Asp Asp Arg Glu 565570 575 Arg Arg Ile Ser His Ser Leu Tyr Ser Gly Ile Glu Gly Leu Asp Glu580 585 590 Ser Pro Ser Arg Asn Ala Ala Leu Ser Arg Ile Met Gly Lys TyrGln 595 600 605 Leu Ser Pro Thr Val Asn Met Pro Gln Asp Asp Thr Val IleIle Glu 610 615 620 Asp Asp Arg Leu Pro Val Leu Pro Pro His Leu Ser AspGln Ser Ser 625 630 635 640 Ser Ser Ser His Asp Asp Val Gly Phe Val ThrAla Asp Ala Gly Thr 645 650 655 Trp Ala Lys Ala Ala Ile Ser Asp Ser AlaAsp Cys Ser Leu Ser Pro 660 665 670 Asp Val Asp Pro Val Leu Ala Phe GlnArg Glu Gly Phe Gly Arg Gln 675 680 685 Thr Asp Glu Thr Lys Leu Asn ThrVal Asp Asp Gln Lys Ala Gly Ser 690 695 700 Pro Ser Arg Asp Val Gly ProSer Leu Gly Leu Lys Lys Ser Ser Ser 705 710 715 720 Leu Glu Ser Leu GlnThr Ala Val Ala Glu Val Thr Leu Asn Gly Asp 725 730 735 Ile Pro Phe HisArg Pro Arg Pro Arg Ile Ile Arg Gly Arg Gly Cys 740 745 750 Asn Glu SerPhe Arg Ala Ala Ile Asp Lys Ser Tyr Asp Lys Pro Ala 755 760 765 Val AspAsp Asp Asp Glu Gly Met Glu Thr Leu Glu Glu Asp Thr Glu 770 775 780 GluSer Ser Arg Ser Gly Arg Glu Ser Val Ser Thr Ala Ser Asp Gln 785 790 795800 Pro Ser His Ser Leu Glu Arg Gln Met Asn Gly Asn Gln Glu Lys Gly 805810 815 Asp Lys Thr Asp Arg Lys Lys Asp Lys Thr Gly Lys Glu Lys Lys Lys820 825 830 Asp Arg Asp Lys Glu Lys Asp Lys Met Lys Ala Lys Lys Gly MetLeu 835 840 845 Lys Gly Leu Gly Asp Met Phe Ser Leu Ala Lys Leu Lys ProGlu Lys 850 855 860 Arg 865 5 30 RNA Artificial Sequence ArtificiallySynthesized Sequence 5 agcaucgagu cggccuuguu ggccuacugg 30 6 42 DNAArtificial Sequence Artificially Synthesized Primer Sequence 6gcggctgaag acggcctatg tggccttttt tttttttttt tt 42 7 21 DNA ArtificialSequence Artificially Synthesized Primer Sequence 7 agcatcgagtcggccttgtt g 21 8 21 DNA Artificial Sequence Artificially SynthesizedPrimer Sequence 8 gcggctgaag acggcctatg t 21 9 433 PRT Homo sapiens 9Met Glu Val Val Asp Pro Gln Gln Leu Gly Met Phe Thr Glu Gly Glu 1 5 1015 Leu Met Ser Val Gly Met Asp Thr Phe Ile His Arg Ile Asp Ser Thr 20 2530 Glu Val Ile Tyr Gln Pro Arg Arg Lys Arg Ala Lys Leu Ile Gly Lys 35 4045 Tyr Leu Met Gly Asp Leu Leu Gly Glu Gly Ser Tyr Gly Lys Val Lys 50 5560 Glu Val Leu Asp Ser Glu Thr Leu Cys Arg Arg Ala Val Lys Ile Leu 65 7075 80 Lys Lys Lys Lys Leu Arg Arg Ile Pro Asn Gly Glu Ala Asn Val Lys 8590 95 Lys Glu Ile Gln Leu Leu Arg Arg Leu Arg His Lys Asn Val Ile Gln100 105 110 Leu Val Asp Val Leu Tyr Asn Glu Glu Lys Gln Lys Met Tyr MetVal 115 120 125 Met Glu Tyr Cys Val Cys Gly Met Gln Glu Met Leu Asp SerVal Pro 130 135 140 Glu Lys Arg Phe Pro Val Cys Gln Ala His Gly Tyr PheCys Gln Leu 145 150 155 160 Ile Asp Gly Leu Glu Tyr Leu His Ser Gln GlyIle Val His Lys Asp 165 170 175 Ile Lys Pro Gly Asn Leu Leu Leu Thr ThrGly Gly Thr Leu Lys Ile 180 185 190 Ser Asp Leu Gly Val Ala Glu Ala LeuHis Pro Phe Ala Ala Asp Asp 195 200 205 Thr Cys Arg Thr Ser Gln Gly SerPro Ala Phe Gln Pro Pro Glu Ile 210 215 220 Ala Asn Gly Leu Asp Thr PheSer Gly Phe Lys Val Asp Ile Trp Ser 225 230 235 240 Ala Gly Val Thr LeuTyr Asn Ile Thr Thr Gly Leu Tyr Pro Phe Glu 245 250 255 Gly Asp Asn IleTyr Lys Leu Phe Glu Asn Ile Gly Lys Gly Ser Tyr 260 265 270 Ala Ile ProGly Asp Cys Gly Pro Pro Leu Ser Asp Leu Leu Lys Gly 275 280 285 Met LeuGlu Tyr Glu Pro Ala Lys Arg Phe Ser Ile Arg Gln Ile Arg 290 295 300 GlnHis Ser Trp Phe Arg Lys Lys His Pro Pro Ala Glu Ala Pro Val 305 310 315320 Pro Ile Pro Pro Ser Pro Asp Thr Lys Asp Arg Trp Arg Ser Met Thr 325330 335 Val Val Pro Tyr Leu Glu Asp Leu His Gly Ala Asp Glu Asp Glu Asp340 345 350 Leu Phe Asp Ile Glu Asp Asp Ile Ile Tyr Thr Gln Asp Phe ThrVal 355 360 365 Pro Gly Gln Val Pro Glu Glu Glu Ala Ser His Asn Gly GlnArg Arg 370 375 380 Gly Leu Pro Lys Ala Val Cys Met Asn Gly Thr Glu AlaAla Gln Leu 385 390 395 400 Ser Thr Lys Ser Arg Ala Glu Gly Arg Ala ProAsn Pro Ala Arg Lys 405 410 415 Ala Cys Ser Ala Ser Ser Lys Ile Arg ArgLeu Ser Ala Cys Lys Gln 420 425 430 Gln 10 396 PRT Homo sapiens 10 MetPro Arg Val Lys Ala Ala Gln Ala Gly Arg Gln Ser Ser Ala Lys 1 5 10 15Arg His Leu Ala Glu Gln Phe Ala Val Gly Glu Ile Ile Thr Asp Met 20 25 30Ala Lys Lys Glu Trp Lys Val Gly Leu Pro Ile Gly Gln Gly Gly Phe 35 40 45Gly Cys Ile Tyr Leu Ala Asp Met Asn Ser Ser Glu Ser Val Gly Ser 50 55 60Asp Ala Pro Cys Val Val Lys Val Glu Pro Ser Asp Asn Gly Pro Leu 65 70 7580 Phe Thr Glu Leu Lys Phe Tyr Gln Arg Ala Ala Lys Pro Glu Gln Ile 85 9095 Gln Lys Trp Ile Arg Thr Arg Lys Leu Lys Tyr Leu Gly Val Pro Lys 100105 110 Tyr Trp Gly Ser Gly Leu His Asp Lys Asn Gly Lys Ser Tyr Arg Phe115 120 125 Met Ile Met Asp Arg Phe Gly Ser Asp Leu Gln Lys Ile Tyr GluAla 130 135 140 Asn Ala Lys Arg Phe Ser Arg Lys Thr Val Leu Gln Leu SerLeu Arg 145 150 155 160 Ile Leu Asp Ile Leu Glu Tyr Ile His Glu His GluTyr Val His Gly 165 170 175 Asp Ile Lys Ala Ser Asn Leu Leu Leu Asn TyrLys Asn Pro Asp Gln 180 185 190 Val Tyr Leu Val Asp Tyr Gly Leu Ala TyrArg Tyr Cys Pro Glu Gly 195 200 205 Val His Lys Glu Tyr Lys Glu Asp ProLys Arg Cys His Asp Gly Thr 210 215 220 Ile Glu Phe Thr Ser Ile Asp AlaHis Asn Gly Val Ala Pro Ser Arg 225 230 235 240 Arg Gly Asp Leu Glu IleLeu Gly Tyr Cys Met Ile Gln Trp Leu Thr 245 250 255 Gly His Leu Pro TrpGlu Asp Asn Leu Lys Asp Pro Lys Tyr Val Arg 260 265 270 Asp Ser Lys IleArg Tyr Arg Glu Asn Ile Ala Ser Leu Met Asp Lys 275 280 285 Cys Phe ProGlu Lys Asn Lys Pro Gly Glu Ile Ala Lys Tyr Met Glu 290 295 300 Thr ValLys Leu Leu Asp Tyr Thr Glu Lys Pro Leu Tyr Glu Asn Leu 305 310 315 320Arg Asp Ile Leu Leu Gln Gly Leu Lys Ala Ile Gly Ser Lys Asp Asp 325 330335 Gly Lys Leu Asp Leu Ser Val Val Glu Asn Gly Gly Leu Lys Ala Lys 340345 350 Thr Ile Thr Lys Lys Arg Lys Lys Glu Ile Glu Glu Ser Lys Glu Pro355 360 365 Gly Val Glu Asp Thr Glu Trp Ser Asn Thr Gln Thr Glu Glu AlaIle 370 375 380 Gln Thr Arg Ser Arg Thr Arg Lys Arg Val Gln Lys 385 390395 11 297 PRT Homo sapiens 11 Met Glu Asp Tyr Thr Lys Ile Glu Lys IleGly Glu Gly Thr Tyr Gly 1 5 10 15 Val Val Tyr Lys Gly Arg His Lys ThrThr Gly Gln Val Val Ala Met 20 25 30 Lys Lys Ile Arg Leu Glu Ser Glu GluGlu Gly Val Pro Ser Thr Ala 35 40 45 Ile Arg Glu Ile Ser Leu Leu Lys GluLeu Arg His Pro Asn Ile Val 50 55 60 Ser Leu Gln Asp Val Leu Met Gln AspSer Arg Leu Tyr Leu Ile Phe 65 70 75 80 Glu Phe Leu Ser Met Asp Leu LysLys Tyr Leu Asp Ser Ile Pro Pro 85 90 95 Gly Gln Tyr Met Asp Ser Ser LeuVal Lys Ser Tyr Leu Tyr Gln Ile 100 105 110 Leu Gln Gly Ile Val Phe CysHis Ser Arg Arg Val Leu His Arg Asp 115 120 125 Leu Lys Pro Gln Asn LeuLeu Ile Asp Asp Lys Gly Thr Ile Lys Leu 130 135 140 Ala Asp Phe Gly LeuAla Arg Ala Phe Gly Ile Pro Ile Arg Val Tyr 145 150 155 160 Thr His GluVal Val Thr Leu Trp Tyr Arg Ser Pro Glu Val Leu Leu 165 170 175 Gly SerAla Arg Tyr Ser Thr Pro Val Asp Ile Trp Ser Ile Gly Thr 180 185 190 IlePhe Ala Glu Leu Ala Thr Lys Lys Pro Leu Phe His Gly Asp Ser 195 200 205Glu Ile Asp Gln Leu Phe Arg Ile Phe Arg Ala Leu Gly Thr Pro Asn 210 215220 Asn Glu Val Trp Pro Glu Val Glu Ser Leu Gln Asp Tyr Lys Asn Thr 225230 235 240 Phe Pro Lys Trp Lys Pro Gly Ser Leu Ala Ser His Val Lys AsnLeu 245 250 255 Asp Glu Asn Gly Leu Asp Leu Leu Ser Lys Met Leu Ile TyrAsp Pro 260 265 270 Ala Lys Arg Ile Ser Gly Lys Met Ala Leu Asn His ProTyr Phe Asn 275 280 285 Asp Leu Asp Asn Gln Ile Lys Lys Met 290 295 12403 PRT Homo sapiens 12 Met Asp Arg Ser Lys Glu Asn Cys Ile Ser Gly ProVal Lys Ala Thr 1 5 10 15 Ala Pro Val Gly Gly Pro Lys Arg Val Leu ValThr Gln Gln Phe Pro 20 25 30 Cys Gln Asn Pro Leu Pro Val Asn Ser Gly GlnAla Gln Arg Val Leu 35 40 45 Cys Pro Ser Asn Ser Ser Gln Arg Ile Pro LeuGln Ala Gln Lys Leu 50 55 60 Val Ser Ser His Lys Pro Val Gln Asn Gln LysGln Lys Gln Leu Gln 65 70 75 80 Ala Thr Ser Val Pro His Pro Val Ser ArgPro Leu Asn Asn Thr Gln 85 90 95 Lys Ser Lys Gln Pro Leu Pro Ser Ala ProGlu Asn Asn Pro Glu Glu 100 105 110 Glu Leu Ala Ser Lys Gln Lys Asn GluGlu Ser Lys Lys Arg Gln Trp 115 120 125 Ala Leu Glu Asp Phe Glu Ile GlyArg Pro Leu Gly Lys Gly Lys Phe 130 135 140 Gly Asn Val Tyr Leu Ala ArgGlu Lys Gln Ser Lys Phe Ile Leu Ala 145 150 155 160 Leu Lys Val Leu PheLys Ala Gln Leu Glu Lys Ala Gly Val Glu His 165 170 175 Gln Leu Arg ArgGlu Val Glu Ile Gln Ser His Leu Arg His Pro Asn 180 185 190 Ile Leu ArgLeu Tyr Gly Tyr Phe His Asp Ala Thr Arg Val Tyr Leu 195 200 205 Ile LeuGlu Tyr Ala Pro Leu Gly Thr Val Tyr Arg Glu Leu Gln Lys 210 215 220 LeuSer Lys Phe Asp Glu Gln Arg Thr Ala Thr Tyr Ile Thr Glu Leu 225 230 235240 Ala Asn Ala Leu Ser Tyr Cys His Ser Lys Arg Val Ile His Arg Asp 245250 255 Ile Lys Pro Glu Asn Leu Leu Leu Gly Ser Ala Gly Glu Leu Lys Ile260 265 270 Ala Asp Phe Gly Trp Ser Val His Ala Pro Ser Ser Arg Arg ThrThr 275 280 285 Leu Cys Gly Thr Leu Asp Tyr Leu Pro Pro Glu Met Ile GluGly Arg 290 295 300 Met His Asp Glu Lys Val Asp Leu Trp Ser Leu Gly ValLeu Cys Tyr 305 310 315 320 Glu Phe Leu Val Gly Lys Pro Pro Phe Glu AlaAsn Thr Tyr Gln Glu 325 330 335 Thr Tyr Lys Arg Ile Ser Arg Val Glu PheThr Phe Pro Asp Phe Val 340 345 350 Thr Glu Gly Ala Arg Asp Leu Ile SerArg Leu Leu Lys His Asn Pro 355 360 365 Ser Gln Arg Pro Met Leu Arg GluVal Leu Glu His Pro Trp Ile Thr 370 375 380 Ala Asn Ser Ser Lys Pro SerAsn Cys Gln Asn Lys Glu Ser Ala Ser 385 390 395 400 Lys Gln Ser 13 344PRT Homo sapiens 13 Met Ala Gln Lys Glu Asn Ser Tyr Pro Trp Pro Tyr GlyArg Gln Thr 1 5 10 15 Ala Pro Ser Gly Leu Ser Thr Leu Pro Gln Arg ValLeu Arg Lys Glu 20 25 30 Pro Val Thr Pro Ser Ala Leu Val Leu Met Ser ArgSer Asn Val Gln 35 40 45 Pro Thr Ala Ala Pro Gly Gln Lys Val Met Glu AsnSer Ser Gly Thr 50 55 60 Pro Asp Ile Leu Thr Arg His Phe Thr Ile Asp AspPhe Glu Ile Gly 65 70 75 80 Arg Pro Leu Gly Lys Gly Lys Phe Gly Asn ValTyr Leu Ala Arg Glu 85 90 95 Lys Lys Ser His Phe Ile Val Ala Leu Lys ValLeu Phe Lys Ser Gln 100 105 110 Ile Glu Lys Glu Gly Val Glu His Gln LeuArg Arg Glu Ile Glu Ile 115 120 125 Gln Ala His Leu His His Pro Asn IleLeu Arg Leu Tyr Asn Tyr Phe 130 135 140 Tyr Asp Arg Arg Arg Ile Tyr LeuIle Leu Glu Tyr Ala Pro Arg Gly 145 150 155 160 Glu Leu Tyr Lys Glu LeuGln Lys Ser Cys Thr Phe Asp Glu Gln Arg 165 170 175 Thr Ala Thr Ile MetGlu Glu Leu Ala Asp Ala Leu Met Tyr Cys His 180 185 190 Gly Lys Lys ValIle His Arg Asp Ile Lys Pro Glu Asn Leu Leu Leu 195 200 205 Gly Leu LysGly Glu Leu Lys Ile Ala Asp Phe Gly Trp Ser Val His 210 215 220 Ala ProSer Leu Arg Arg Lys Thr Met Cys Gly Thr Leu Asp Tyr Leu 225 230 235 240Pro Pro Glu Met Ile Glu Gly Arg Met His Asn Glu Lys Val Asp Leu 245 250255 Trp Cys Ile Gly Val Leu Cys Tyr Glu Leu Leu Val Gly Asn Pro Pro 260265 270 Phe Glu Ser Ala Ser His Asn Glu Thr Tyr Arg Arg Ile Val Lys Val275 280 285 Asp Leu Lys Phe Pro Ala Ser Val Pro Thr Gly Ala Gln Asp LeuIle 290 295 300 Ser Lys Leu Leu Arg His Asn Pro Ser Glu Arg Leu Pro LeuAla Gln 305 310 315 320 Val Ser Ala His Pro Trp Val Arg Ala Asn Ser ArgArg Val Leu Pro 325 330 335 Pro Ser Ala Leu Gln Ser Val Ala 340 14 745PRT Homo sapiens 14 Met Glu Arg Pro Pro Gly Leu Arg Pro Gly Ala Gly GlyPro Trp Glu 1 5 10 15 Met Arg Glu Arg Leu Gly Thr Gly Gly Phe Gly AsnVal Cys Leu Tyr 20 25 30 Gln His Arg Glu Leu Asp Leu Lys Ile Ala Ile LysSer Cys Arg Leu 35 40 45 Glu Leu Ser Thr Lys Asn Arg Glu Arg Trp Cys HisGlu Ile Gln Ile 50 55 60 Met Lys Lys Leu Asn His Ala Asn Val Val Lys AlaCys Asp Val Pro 65 70 75 80 Glu Glu Leu Asn Ile Leu Ile His Asp Val ProLeu Leu Ala Met Glu 85 90 95 Tyr Cys Ser Gly Gly Asp Leu Arg Lys Leu LeuAsn Lys Pro Glu Asn 100 105 110 Cys Cys Gly Leu Lys Glu Ser Gln Ile LeuSer Leu Leu Ser Asp Ile 115 120 125 Gly Ser Gly Ile Arg Tyr Leu His GluAsn Lys Ile Ile His Arg Asp 130 135 140 Leu Lys Pro Glu Asn Ile Val LeuGln Asp Val Gly Gly Lys Ile Ile 145 150 155 160 His Lys Ile Ile Asp LeuGly Tyr Ala Lys Asp Val Asp Gln Gly Ser 165 170 175 Leu Cys Thr Ser PheVal Gly Thr Leu Gln Tyr Leu Ala Pro Glu Leu 180 185 190 Phe Glu Asn LysPro Tyr Thr Ala Thr Val Asp Tyr Trp Ser Phe Gly 195 200 205 Thr Met ValPhe Glu Cys Ile Ala Gly Tyr Arg Pro Phe Leu His His 210 215 220 Leu GlnPro Phe Thr Trp His Glu Lys Ile Lys Lys Lys Asp Pro Lys 225 230 235 240Cys Ile Phe Ala Cys Glu Glu Met Ser Gly Glu Val Arg Phe Ser Ser 245 250255 His Leu Pro Gln Pro Asn Ser Leu Cys Ser Leu Ile Val Glu Pro Met 260265 270 Glu Asn Trp Leu Gln Leu Met Leu Asn Trp Asp Pro Gln Gln Arg Gly275 280 285 Gly Pro Val Asp Leu Thr Leu Lys Gln Pro Arg Cys Phe Val LeuMet 290 295 300 Asp His Ile Leu Asn Leu Lys Ile Val His Ile Leu Asn MetThr Ser 305 310 315 320 Ala Lys Ile Ile Ser Phe Leu Leu Pro Pro Asp GluSer Leu His Ser 325 330 335 Leu Gln Ser Arg Ile Glu Arg Glu Thr Gly IleAsn Thr Gly Ser Gln 340 345 350 Glu Leu Leu Ser Glu Thr Gly Ile Ser LeuAsp Pro Arg Lys Pro Ala 355 360 365 Ser Gln Cys Val Leu Asp Gly Val ArgGly Cys Asp Ser Tyr Met Val 370 375 380 Tyr Leu Phe Asp Lys Ser Lys ThrVal Tyr Glu Gly Pro Phe Ala Ser 385 390 395 400 Arg Ser Leu Ser Asp CysVal Asn Tyr Ile Val Gln Asp Ser Lys Ile 405 410 415 Gln Leu Pro Ile IleGln Leu Arg Lys Val Trp Ala Glu Ala Val His 420 425 430 Tyr Val Ser GlyLeu Lys Glu Asp Tyr Ser Arg Leu Phe Gln Gly Gln 435 440 445 Arg Ala AlaMet Leu Ser Leu Leu Arg Tyr Asn Ala Asn Leu Thr Lys 450 455 460 Met LysAsn Thr Leu Ile Ser Ala Ser Gln Gln Leu Lys Ala Lys Leu 465 470 475 480Glu Phe Phe His Lys Ser Ile Gln Leu Asp Leu Glu Arg Tyr Ser Glu 485 490495 Gln Met Thr Tyr Gly Ile Ser Ser Glu Lys Met Leu Lys Ala Trp Lys 500505 510 Glu Met Glu Glu Lys Ala Ile His Tyr Ala Glu Val Gly Val Ile Gly515 520 525 Tyr Leu Glu Asp Gln Ile Met Ser Leu His Ala Glu Ile Met GluLeu 530 535 540 Gln Lys Ser Pro Tyr Gly Arg Arg Gln Gly Asp Leu Met GluSer Leu 545 550 555 560 Glu Gln Arg Ala Ile Asp Leu Tyr Lys Gln Leu LysHis Arg Pro Ser 565 570 575 Asp His Ser Tyr Ser Asp Ser Thr Glu Met ValLys Ile Ile Val His 580 585 590 Thr Val Gln Ser Gln Asp Arg Val Leu LysGlu Leu Phe Gly His Leu 595 600 605 Ser Lys Leu Leu Gly Cys Lys Gln LysIle Ile Asp Leu Leu Pro Lys 610 615 620 Val Glu Val Ala Leu Ser Asn IleLys Glu Ala Asp Asn Thr Val Met 625 630 635 640 Phe Met Gln Gly Lys ArgGln Lys Glu Ile Trp His Leu Leu Lys Ile 645 650 655 Ala Cys Thr Gln SerSer Ala Arg Ser Leu Val Gly Ser Ser Leu Glu 660 665 670 Gly Ala Val ThrPro Gln Thr Ser Ala Trp Leu Pro Pro Thr Ser Ala 675 680 685 Glu His AspHis Ser Leu Ser Cys Val Val Thr Pro Gln Asp Gly Glu 690 695 700 Thr SerAla Gln Met Ile Glu Glu Asn Leu Asn Cys Leu Gly His Leu 705 710 715 720Ser Thr Ile Ile His Glu Ala Asn Glu Glu Gln Gly Asn Ser Met Met 725 730735 Asn Leu Asp Trp Ser Trp Leu Thr Glu 740 745 15 318 PRT Homo sapiens15 Met Ser Lys Pro Pro Ala Pro Asn Pro Thr Pro Pro Arg Asn Leu Asp 1 510 15 Ser Arg Thr Phe Ile Thr Ile Gly Asp Arg Asn Phe Glu Val Glu Ala 2025 30 Asp Asp Leu Val Thr Ile Ser Glu Leu Gly Arg Gly Ala Tyr Gly Val 3540 45 Val Glu Lys Val Arg His Ala Gln Ser Gly Thr Ile Met Ala Val Lys 5055 60 Arg Ile Arg Ala Thr Val Asn Ser Gln Glu Gln Lys Arg Leu Leu Met 6570 75 80 Asp Leu Asp Ile Asn Met Arg Thr Val Asp Cys Phe Tyr Thr Val Thr85 90 95 Phe Tyr Gly Ala Leu Phe Arg Glu Gly Asp Val Trp Ile Cys Met Glu100 105 110 Leu Met Asp Thr Ser Leu Asp Lys Phe Tyr Arg Lys Val Leu AspLys 115 120 125 Asn Met Thr Ile Pro Glu Asp Ile Leu Gly Glu Ile Ala ValSer Ile 130 135 140 Val Arg Ala Leu Glu His Leu His Ser Lys Leu Ser ValIle His Arg 145 150 155 160 Asp Val Lys Pro Ser Asn Val Leu Ile Asn LysGlu Gly His Val Lys 165 170 175 Met Cys Asp Phe Gly Ile Ser Gly Tyr LeuVal Asp Ser Val Ala Lys 180 185 190 Thr Met Asp Ala Gly Cys Lys Pro TyrMet Ala Pro Glu Arg Ile Asn 195 200 205 Pro Glu Leu Asn Gln Lys Gly TyrAsn Val Lys Ser Asp Val Trp Ser 210 215 220 Leu Gly Ile Thr Met Ile GluMet Ala Ile Leu Arg Phe Pro Tyr Glu 225 230 235 240 Ser Trp Gly Thr ProPhe Gln Gln Leu Lys Gln Val Val Glu Glu Pro 245 250 255 Ser Pro Gln LeuPro Ala Asp Arg Phe Ser Pro Glu Phe Val Asp Phe 260 265 270 Thr Ala GlnCys Leu Arg Lys Asn Pro Ala Glu Arg Met Ser Tyr Leu 275 280 285 Glu LeuMet Glu His Pro Phe Phe Thr Leu His Lys Thr Lys Lys Thr 290 295 300 AspIle Ala Ala Phe Val Lys Lys Ile Leu Gly Glu Asp Ser 305 310 315 16 379PRT Homo sapiens 16 Met Ala Ala Ala Ala Ala Gln Gly Gly Gly Gly Gly GluPro Arg Arg 1 5 10 15 Thr Glu Gly Val Gly Pro Gly Val Pro Gly Glu ValGlu Met Val Lys 20 25 30 Gly Gln Pro Phe Asp Val Gly Pro Arg Tyr Thr GlnLeu Gln Tyr Ile 35 40 45 Gly Glu Gly Ala Tyr Gly Met Val Ser Ser Ala TyrAsp His Val Arg 50 55 60 Lys Thr Arg Val Ala Ile Lys Lys Ile Ser Pro PheGlu His Gln Thr 65 70 75 80 Tyr Cys Gln Arg Thr Leu Arg Glu Ile Gln IleLeu Leu Arg Phe Arg 85 90 95 His Glu Asn Val Ile Gly Ile Arg Asp Ile LeuArg Ala Ser Thr Leu 100 105 110 Glu Ala Met Arg Asp Val Tyr Ile Val GlnAsp Leu Met Glu Thr Asp 115 120 125 Leu Tyr Lys Leu Leu Lys Ser Gln GlnLeu Ser Asn Asp His Ile Cys 130 135 140 Tyr Phe Leu Tyr Gln Ile Leu ArgGly Leu Lys Tyr Ile His Ser Ala 145 150 155 160 Asn Val Leu His Arg AspLeu Lys Pro Ser Asn Leu Leu Ser Asn Thr 165 170 175 Thr Cys Asp Leu LysIle Cys Asp Phe Gly Leu Ala Arg Ile Ala Asp 180 185 190 Pro Glu His AspHis Thr Gly Phe Leu Thr Glu Tyr Val Ala Thr Arg 195 200 205 Trp Tyr ArgAla Pro Glu Ile Met Leu Asn Ser Lys Gly Tyr Thr Lys 210 215 220 Ser IleAsp Ile Trp Ser Val Gly Cys Ile Leu Ala Glu Met Leu Ser 225 230 235 240Asn Arg Pro Ile Phe Pro Gly Lys His Tyr Leu Asp Gln Leu Asn His 245 250255 Ile Leu Gly Ile Leu Gly Ser Pro Ser Gln Glu Asp Leu Asn Cys Ile 260265 270 Ile Asn Met Lys Ala Arg Asn Tyr Leu Gln Ser Leu Pro Ser Lys Thr275 280 285 Lys Val Ala Trp Ala Lys Leu Phe Pro Lys Ser Asp Ser Lys AlaLeu 290 295 300 Asp Leu Leu Asp Arg Met Leu Thr Phe Asn Pro Asn Lys ArgIle Thr 305 310 315 320 Val Glu Glu Ala Leu Ala His Pro Tyr Leu Glu GlnTyr Tyr Asp Pro 325 330 335 Thr Asp Glu Pro Val Ala Glu Glu Pro Phe ThrPhe Ala Met Glu Leu 340 345 350 Asp Asp Leu Pro Lys Glu Arg Leu Lys GluLeu Ile Phe Gln Glu Thr 355 360 365 Ala Arg Phe Gln Pro Gly Val Leu GluAla Pro 370 375 17 648 PRT Homo sapiens 17 Met Glu His Ile Gln Gly AlaTrp Lys Thr Ile Ser Asn Gly Phe Gly 1 5 10 15 Phe Lys Asp Ala Val PheAsp Gly Ser Ser Cys Ile Ser Pro Thr Ile 20 25 30 Val Gln Gln Phe Gly TyrGln Arg Arg Ala Ser Asp Asp Gly Lys Leu 35 40 45 Thr Asp Pro Ser Lys ThrSer Asn Thr Ile Arg Val Phe Leu Pro Asn 50 55 60 Lys Gln Arg Thr Val ValAsn Val Arg Asn Gly Met Ser Leu His Asp 65 70 75 80 Cys Leu Met Lys AlaLeu Lys Val Arg Gly Leu Gln Pro Glu Cys Cys 85 90 95 Ala Val Phe Arg LeuLeu His Glu His Lys Gly Lys Lys Ala Arg Leu 100 105 110 Asp Trp Asn ThrAsp Ala Ala Ser Leu Ile Gly Glu Glu Leu Gln Val 115 120 125 Asp Phe LeuAsp His Val Pro Leu Thr Thr His Asn Phe Ala Arg Lys 130 135 140 Thr PheLeu Lys Leu Ala Phe Cys Asp Ile Cys Gln Lys Phe Leu Leu 145 150 155 160Asn Gly Phe Arg Cys Gln Thr Cys Gly Tyr Lys Phe His Glu His Cys 165 170175 Ser Thr Lys Val Pro Thr Met Cys Val Asp Trp Ser Asn Ile Arg Gln 180185 190 Leu Leu Leu Phe Pro Asn Ser Thr Ile Gly Asp Ser Gly Val Pro Ala195 200 205 Leu Pro Ser Leu Thr Met Arg Arg Met Arg Glu Ser Val Ser ArgMet 210 215 220 Pro Val Ser Ser Gln His Arg Tyr Ser Thr Pro His Ala PheThr Phe 225 230 235 240 Asn Thr Ser Ser Pro Ser Ser Glu Gly Ser Leu SerGln Arg Gln Arg 245 250 255 Ser Thr Ser Thr Pro Asn Val His Met Val SerThr Thr Leu Pro Val 260 265 270 Asp Ser Arg Met Ile Glu Asp Ala Ile ArgSer His Ser Glu Ser Ala 275 280 285 Ser Pro Ser Ala Leu Ser Ser Ser ProAsn Asn Leu Ser Pro Thr Gly 290 295 300 Trp Ser Gln Pro Lys Thr Pro ValPro Ala Gln Arg Glu Arg Ala Pro 305 310 315 320 Val Ser Gly Thr Gln GluLys Asn Lys Ile Arg Pro Arg Gly Gln Arg 325 330 335 Asp Ser Ser Tyr TyrTrp Glu Ile Glu Ala Ser Glu Val Met Leu Ser 340 345 350 Thr Arg Ile GlySer Gly Ser Phe Gly Thr Val Tyr Lys Gly Lys Trp 355 360 365 His Gly AspVal Ala Val Lys Ile Leu Lys Val Val Asp Pro Thr Pro 370 375 380 Glu GlnPhe Gln Ala Phe Arg Asn Glu Val Ala Val Leu Arg Lys Thr 385 390 395 400Arg His Val Asn Ile Leu Leu Phe Met Gly Tyr Met Thr Lys Asp Asn 405 410415 Leu Ala Ile Val Thr Gln Trp Cys Glu Gly Ser Ser Leu Tyr Lys His 420425 430 Leu His Val Gln Glu Thr Lys Phe Gln Met Phe Gln Leu Ile Asp Ile435 440 445 Ala Arg Gln Thr Ala Gln Gly Met Asp Tyr Leu His Ala Lys AsnIle 450 455 460 Ile His Arg Asp Met Lys Ser Asn Asn Ile Phe Leu His GluGly Leu 465 470 475 480 Thr Val Lys Ile Gly Asp Phe Gly Leu Ala Thr ValLys Ser Arg Trp 485 490 495 Ser Gly Ser Gln Gln Val Glu Gln Pro Thr GlySer Val Leu Trp Met 500 505 510 Ala Pro Glu Val Ile Arg Met Gln Asp AsnAsn Pro Phe Ser Phe Gln 515 520 525 Ser Asp Val Tyr Ser Tyr Gly Ile ValLeu Tyr Glu Leu Met Thr Gly 530 535 540 Glu Leu Pro Tyr Ser His Ile AsnAsn Arg Asp Gln Ile Ile Phe Met 545 550 555 560 Val Gly Arg Gly Tyr AlaSer Pro Asp Leu Ser Lys Leu Tyr Lys Asn 565 570 575 Cys Pro Lys Ala MetLys Arg Leu Val Ala Asp Cys Val Lys Lys Val 580 585 590 Lys Glu Glu ArgPro Leu Phe Pro Gln Ile Leu Ser Ser Ile Glu Leu 595 600 605 Leu Gln HisSer Leu Pro Lys Ile Asn Arg Ser Ala Ser Glu Pro Ser 610 615 620 Leu HisArg Ala Ala His Thr Glu Asp Ile Asn Ala Cys Thr Leu Thr 625 630 635 640Thr Ser Pro Arg Leu Pro Val Phe 645 18 480 PRT Homo sapiens 18 Met SerAsp Val Ala Ile Val Lys Glu Gly Trp Leu His Lys Arg Gly 1 5 10 15 GluTyr Ile Lys Thr Trp Arg Pro Arg Tyr Phe Leu Leu Lys Asn Asp 20 25 30 GlyThr Phe Ile Gly Tyr Lys Glu Arg Pro Gln Asp Val Asp Gln Arg 35 40 45 GluAla Pro Leu Asn Asn Phe Ser Val Ala Gln Cys Gln Leu Met Lys 50 55 60 ThrGlu Arg Pro Arg Pro Asn Thr Phe Ile Ile Arg Cys Leu Gln Trp 65 70 75 80Thr Thr Val Ile Glu Arg Thr Phe His Val Glu Thr Pro Glu Glu Arg 85 90 95Glu Glu Trp Thr Thr Ala Ile Gln Thr Val Ala Asp Gly Leu Lys Lys 100 105110 Gln Glu Glu Glu Glu Met Asp Phe Arg Ser Gly Ser Pro Ser Asp Asn 115120 125 Ser Gly Ala Glu Glu Met Glu Val Ser Leu Ala Lys Pro Lys His Arg130 135 140 Val Thr Met Asn Glu Phe Glu Tyr Leu Lys Leu Leu Gly Lys GlyThr 145 150 155 160 Phe Gly Lys Val Ile Leu Val Lys Glu Lys Ala Thr GlyArg Tyr Tyr 165 170 175 Ala Met Lys Ile Leu Lys Lys Glu Val Ile Val AlaLys Asp Glu Val 180 185 190 Ala His Thr Leu Thr Glu Asn Arg Val Leu GlnAsn Ser Arg His Pro 195 200 205 Phe Leu Thr Ala Leu Lys Tyr Ser Phe GlnThr His Asp Arg Leu Cys 210 215 220 Phe Val Met Glu Tyr Ala Asn Gly GlyGlu Leu Phe Phe His Leu Ser 225 230 235 240 Arg Glu Arg Val Phe Ser GluAsp Arg Ala Arg Phe Tyr Gly Ala Glu 245 250 255 Ile Val Ser Ala Leu AspTyr Leu His Ser Glu Lys Asn Val Val Tyr 260 265 270 Arg Asp Leu Lys LeuGlu Asn Leu Met Leu Asp Lys Asp Gly His Ile 275 280 285 Lys Ile Thr AspPhe Gly Leu Cys Lys Glu Gly Ile Lys Asp Gly Ala 290 295 300 Thr Met LysThr Phe Cys Gly Thr Pro Glu Tyr Leu Ala Pro Glu Val 305 310 315 320 LeuGlu Asp Asn Asp Tyr Gly Arg Ala Val Asp Trp Trp Gly Leu Gly 325 330 335Val Val Met Tyr Glu Met Met Cys Gly Arg Leu Pro Phe Tyr Asn Gln 340 345350 Asp His Glu Lys Leu Phe Glu Leu Ile Leu Met Glu Glu Ile Arg Phe 355360 365 Pro Arg Thr Leu Gly Pro Glu Ala Lys Ser Leu Leu Ser Gly Leu Leu370 375 380 Lys Lys Asp Pro Lys Gln Arg Leu Gly Gly Gly Ser Glu Asp AlaLys 385 390 395 400 Glu Ile Met Gln His Arg Phe Phe Ala Gly Ile Val TrpGln His Val 405 410 415 Tyr Glu Lys Lys Leu Ser Pro Pro Phe Lys Pro GlnVal Thr Ser Glu 420 425 430 Thr Asp Thr Arg Tyr Phe Asp Glu Glu Phe ThrAla Gln Met Ile Thr 435 440 445 Ile Thr Pro Pro Asp Gln Asp Asp Ser MetGlu Cys Val Asp Ser Glu 450 455 460 Arg Arg Pro His Phe Pro Gln Phe SerTyr Ser Ala Ser Ser Thr Ala 465 470 475 480 19 724 PRT Homo sapiens 19Met Ser Ala Glu Gly Tyr Gln Tyr Arg Ala Leu Tyr Asp Tyr Lys Lys 1 5 1015 Glu Arg Glu Glu Asp Ile Asp Leu His Leu Gly Asp Ile Leu Thr Val 20 2530 Asn Lys Gly Ser Leu Val Ala Leu Gly Phe Ser Asp Gly Gln Glu Ala 35 4045 Arg Pro Glu Glu Ile Gly Trp Leu Asn Gly Tyr Asn Glu Thr Thr Gly 50 5560 Glu Arg Gly Asp Phe Pro Gly Thr Tyr Val Glu Tyr Ile Gly Arg Lys 65 7075 80 Lys Ile Ser Pro Pro Thr Pro Lys Pro Arg Pro Pro Arg Pro Leu Pro 8590 95 Val Ala Pro Gly Ser Ser Lys Thr Glu Ala Asp Val Glu Gln Gln Ala100 105 110 Leu Thr Leu Pro Asp Leu Ala Glu Gln Phe Ala Pro Pro Asp IleAla 115 120 125 Pro Pro Leu Leu Ile Lys Leu Val Glu Ala Ile Glu Lys LysGly Leu 130 135 140 Glu Cys Ser Thr Leu Tyr Arg Thr Gln Ser Ser Ser AsnLeu Ala Glu 145 150 155 160 Leu Arg Gln Leu Leu Asp Cys Asp Thr Pro SerVal Asp Leu Glu Met 165 170 175 Ile Asp Val His Val Leu Ala Asp Ala PheLys Arg Tyr Leu Leu Asp 180 185 190 Leu Pro Asn Pro Val Ile Pro Ala AlaVal Tyr Ser Glu Met Ile Ser 195 200 205 Leu Ala Pro Glu Val Gln Ser SerGlu Glu Tyr Ile Gln Leu Leu Lys 210 215 220 Lys Leu Ile Arg Ser Pro SerIle Pro His Gln Tyr Trp Leu Thr Leu 225 230 235 240 Gln Tyr Leu Leu LysHis Phe Phe Lys Leu Ser Gln Thr Ser Ser Lys 245 250 255 Asn Leu Leu AsnAla Arg Val Leu Ser Glu Ile Phe Ser Pro Met Leu 260 265 270 Phe Arg PheSer Ala Ala Ser Ser Asp Asn Thr Glu Asn Leu Ile Lys 275 280 285 Val IleGlu Ile Leu Ile Ser Thr Glu Trp Asn Glu Arg Gln Pro Ala 290 295 300 ProAla Leu Pro Pro Lys Pro Pro Lys Pro Thr Thr Val Ala Asn Asn 305 310 315320 Gly Met Asn Asn Asn Met Ser Leu Gln Asn Ala Glu Trp Tyr Trp Gly 325330 335 Asp Ile Ser Arg Glu Glu Val Asn Glu Lys Leu Arg Asp Thr Ala Asp340 345 350 Gly Thr Phe Leu Val Arg Asp Ala Ser Thr Lys Met His Gly AspTyr 355 360 365 Thr Leu Thr Leu Arg Lys Gly Gly Asn Asn Lys Leu Ile LysIle Phe 370 375 380 His Arg Asp Gly Lys Tyr Gly Phe Ser Asp Pro Leu ThrPhe Ser Ser 385 390 395 400 Val Val Glu Leu Ile Asn His Tyr Arg Asn GluSer Leu Ala Gln Tyr 405 410 415 Asn Pro Lys Leu Asp Val Lys Leu Leu TyrPro Val Ser Lys Tyr Gln 420 425 430 Gln Asp Gln Val Val Lys Glu Asp AsnIle Glu Ala Val Gly Lys Lys 435 440 445 Leu His Glu Tyr Asn Thr Gln PheGln Glu Lys Ser Arg Glu Tyr Asp 450 455 460 Arg Leu Tyr Glu Glu Tyr ThrArg Thr Ser Gln Glu Ile Gln Met Lys 465 470 475 480 Arg Thr Ala Ile GluAla Phe Asn Glu Thr Ile Lys Ile Phe Glu Glu 485 490 495 Gln Cys Gln ThrGln Glu Arg Tyr Ser Lys Glu Tyr Ile Glu Lys Phe 500 505 510 Lys Arg GluGly Asn Glu Lys Glu Ile Gln Arg Ile Met His Asn Tyr 515 520 525 Asp LysLeu Lys Ser Arg Ile Ser Glu Ile Ile Asp Ser Arg Arg Arg 530 535 540 LeuGlu Glu Asp Leu Lys Lys Gln Ala Ala Glu Tyr Arg Glu Ile Asp 545 550 555560 Lys Arg Met Asn Ser Ile Lys Pro Asp Leu Ile Gln Leu Arg Lys Thr 565570 575 Arg Asp Gln Tyr Leu Met Trp Leu Thr Gln Lys Gly Val Arg Gln Lys580 585 590 Lys Leu Asn Glu Trp Leu Gly Asn Glu Asn Thr Glu Asp Gln TyrSer 595 600 605 Leu Val Glu Asp Asp Glu Asp Leu Pro His His Asp Glu LysThr Trp 610 615 620 Asn Val Gly Ser Ser Asn Arg Asn Lys Ala Glu Asn LeuLeu Arg Gly 625 630 635 640 Lys Arg Asp Gly Thr Phe Leu Val Arg Glu SerSer Lys Gln Gly Cys 645 650 655 Tyr Ala Cys Ser Val Val Val Asp Gly GluVal Lys His Cys Val Ile 660 665 670 Asn Lys Thr Ala Thr Gly Tyr Gly PheAla Glu Pro Tyr Asn Leu Tyr 675 680 685 Ser Ser Leu Lys Glu Leu Val LeuHis Tyr Gln His Thr Ser Leu Val 690 695 700 Gln His Asn Asp Ser Leu AsnVal Thr Leu Ala Tyr Pro Val Tyr Ala 705 710 715 720 Gln Gln Arg Arg 203056 PRT Homo sapiens 20 Met Ser Leu Val Leu Asn Asp Leu Leu Ile Cys CysArg Gln Leu Glu 1 5 10 15 His Asp Arg Ala Thr Glu Arg Lys Lys Glu ValGlu Lys Phe Lys Arg 20 25 30 Leu Ile Arg Asp Pro Glu Thr Ile Lys His LeuAsp Arg His Ser Asp 35 40 45 Ser Lys Gln Gly Lys Tyr Leu Asn Trp Asp AlaVal Phe Arg Phe Leu 50 55 60 Gln Lys Tyr Ile Gln Lys Glu Thr Glu Cys LeuArg Ile Ala Lys Pro 65 70 75 80 Asn Val Ser Ala Ser Thr Gln Ala Ser ArgGln Lys Lys Met Gln Glu 85 90 95 Ile Ser Ser Leu Val Lys Tyr Phe Ile LysCys Ala Asn Arg Arg Ala 100 105 110 Pro Arg Leu Lys Cys Gln Glu Leu LeuAsn Tyr Ile Met Asp Thr Val 115 120 125 Lys Asp Ser Ser Asn Gly Ala IleTyr Gly Ala Asp Cys Ser Asn Ile 130 135 140 Leu Leu Lys Asp Ile Leu SerVal Arg Lys Tyr Trp Cys Glu Ile Ser 145 150 155 160 Gln Gln Gln Trp LeuGlu Leu Phe Ser Val Tyr Phe Arg Leu Tyr Leu 165 170 175 Lys Pro Ser GlnAsp Val His Arg Val Leu Val Ala Arg Ile Ile His 180 185 190 Ala Val ThrLys Gly Cys Cys Ser Gln Thr Asp Gly Leu Asn Ser Lys 195 200 205 Phe LeuAsp Phe Phe Ser Lys Ala Ile Gln Cys Ala Arg Gln Glu Lys 210 215 220 SerSer Ser Gly Leu Asn His Ile Leu Ala Ala Leu Thr Ile Phe Leu 225 230 235240 Lys Thr Leu Ala Val Asn Phe Arg Ile Arg Val Cys Glu Leu Gly Asp 245250 255 Glu Ile Leu Pro Thr Leu Leu Tyr Ile Trp Thr Gln His Arg Leu Asn260 265 270 Asp Ser Leu Lys Glu Val Ile Ile Glu Leu Phe Gln Leu Gln IleTyr 275 280 285 Ile His His Pro Lys Gly Ala Lys Thr Gln Glu Lys Gly AlaTyr Glu 290 295 300 Ser Thr Lys Trp Arg Ser Ile Leu Tyr Asn Leu Tyr AspLeu Leu Val 305 310 315 320 Asn Glu Ile Ser His Ile Gly Ser Arg Gly LysTyr Ser Ser Gly Phe 325 330 335 Arg Asn Ile Ala Val Lys Glu Asn Leu IleGlu Leu Met Ala Asp Ile 340 345 350 Cys His Gln Val Phe Asn Glu Asp ThrArg Ser Leu Glu Ile Ser Gln 355 360 365 Ser Tyr Thr Thr Thr Gln Arg GluSer Ser Asp Tyr Ser Val Pro Cys 370 375 380 Lys Arg Lys Lys Ile Glu LeuGly Trp Glu Val Ile Lys Asp His Leu 385 390 395 400 Gln Lys Ser Gln AsnAsp Phe Asp Leu Val Pro Trp Leu Gln Ile Ala 405 410 415 Thr Gln Leu IleSer Lys Tyr Pro Ala Ser Leu Pro Asn Cys Glu Leu 420 425 430 Ser Pro LeuLeu Met Ile Leu Ser Gln Leu Leu Pro Gln Gln Arg His 435 440 445 Gly GluArg Thr Pro Tyr Val Leu Arg Cys Leu Thr Glu Val Ala Leu 450 455 460 CysGln Asp Lys Arg Ser Asn Leu Glu Ser Ser Gln Lys Ser Asp Leu 465 470 475480 Leu Lys Leu Trp Asn Lys Ile Trp Cys Ile Thr Phe Arg Gly Ile Ser 485490 495 Ser Glu Gln Ile Gln Ala Glu Asn Phe Gly Leu Leu Gly Ala Ile Ile500 505 510 Gln Gly Ser Leu Val Glu Val Asp Arg Glu Phe Trp Lys Leu PheThr 515 520 525 Gly Ser Ala Cys Arg Pro Ser Cys Pro Ala Val Cys Cys LeuThr Leu 530 535 540 Ala Leu Thr Thr Ser Ile Val Pro Gly Ala Val Lys MetGly Ile Glu 545 550 555 560 Gln Asn Met Cys Glu Val Asn Arg Ser Phe SerLeu Lys Glu Ser Ile 565 570 575 Met Lys Trp Leu Leu Phe Tyr Gln Leu GluGly Asp Leu Glu Asn Ser 580 585 590 Thr Glu Val Pro Pro Ile Leu His SerAsn Phe Pro His Leu Val Leu 595 600 605 Glu Lys Ile Leu Val Ser Leu ThrMet Lys Asn Cys Lys Ala Ala Met 610 615 620 Asn Phe Phe Gln Ser Val ProGlu Cys Glu His His Gln Lys Asp Lys 625 630 635 640 Glu Glu Leu Ser PheSer Glu Val Glu Glu Leu Phe Leu Gln Thr Thr 645 650 655 Phe Asp Lys MetAsp Phe Leu Thr Ile Val Arg Glu Cys Gly Ile Glu 660 665 670 Lys His GlnSer Ser Ile Gly Phe Ser Val His Gln Asn Leu Lys Glu 675 680 685 Ser LeuAsp Arg Cys Leu Leu Gly Leu Ser Glu Gln Leu Leu Asn Asn 690 695 700 TyrSer Ser Glu Ile Thr Asn Ser Glu Thr Leu Val Arg Cys Ser Arg 705 710 715720 Leu Leu Val Gly Val Leu Gly Cys Tyr Cys Tyr Met Gly Val Ile Ala 725730 735 Glu Glu Glu Ala Tyr Lys Ser Glu Leu Phe Gln Lys Ala Asn Ser Leu740 745 750 Met Gln Cys Ala Gly Glu Ser Ile Thr Leu Phe Lys Asn Lys ThrAsn 755 760 765 Glu Glu Phe Arg Ile Gly Ser Leu Arg Asn Met Met Gln LeuCys Thr 770 775 780 Arg Cys Leu Ser Asn Cys Thr Lys Lys Ser Pro Asn LysIle Ala Ser 785 790 795 800 Gly Phe Phe Leu Arg Leu Leu Thr Ser Lys LeuMet Asn Asp Ile Ala 805 810 815 Asp Ile Cys Lys Ser Leu Ala Ser Phe IleLys Lys Pro Phe Asp Arg 820 825 830 Gly Glu Val Glu Ser Met Glu Asp AspThr Asn Gly Asn Leu Met Glu 835 840 845 Val Glu Asp Gln Ser Ser Met AsnLeu Phe Asn Asp Tyr Pro Asp Ser 850 855 860 Ser Val Ser Asp Ala Asn GluPro Gly Glu Ser Gln Ser Thr Ile Gly 865 870 875 880 Ala Ile Asn Pro LeuAla Glu Glu Tyr Leu Ser Lys Gln Asp Leu Leu 885 890 895 Phe Leu Asp MetLeu Lys Phe Leu Cys Leu Cys Val Thr Thr Ala Gln 900 905 910 Thr Asn ThrVal Ser Phe Arg Ala Ala Asp Ile Arg Arg Lys Leu Leu 915 920 925 Met LeuIle Asp Ser Ser Thr Leu Glu Pro Thr Lys Ser Leu His Leu 930 935 940 HisMet Tyr Leu Met Leu Leu Lys Glu Leu Pro Gly Glu Glu Tyr Pro 945 950 955960 Leu Pro Met Glu Asp Val Leu Glu Leu Leu Lys Pro Leu Ser Asn Val 965970 975 Cys Ser Leu Tyr Arg Arg Asp Gln Asp Val Cys Lys Thr Ile Leu Asn980 985 990 His Val Leu His Val Val Lys Asn Leu Gly Gln Ser Asn Met AspSer 995 1000 1005 Glu Asn Thr Arg Asp Ala Gln Gly Gln Phe Leu Thr ValIle Gly Ala 1010 1015 1020 Phe Trp His Leu Thr Lys Glu Arg Lys Tyr IlePhe Ser Val Arg Met 1025 1030 1035 1040 Ala Leu Val Asn Cys Leu Lys ThrLeu Leu Glu Ala Asp Pro Tyr Ser 1045 1050 1055 Lys Trp Ala Ile Leu AsnVal Met Gly Lys Asp Phe Pro Val Asn Glu 1060 1065 1070 Val Phe Thr GlnPhe Leu Ala Asp Asn His His Gln Val Arg Met Leu 1075 1080 1085 Ala AlaGlu Ser Ile Asn Arg Leu Phe Gln Asp Thr Lys Gly Asp Ser 1090 1095 1100Ser Arg Leu Leu Lys Ala Leu Pro Leu Lys Leu Gln Gln Thr Ala Phe 11051110 1115 1120 Glu Asn Ala Tyr Leu Lys Ala Gln Glu Gly Met Arg Glu MetSer His 1125 1130 1135 Ser Ala Glu Asn Pro Glu Thr Leu Asp Glu Ile TyrAsn Arg Lys Ser 1140 1145 1150 Val Leu Leu Thr Leu Ile Ala Val Val LeuSer Cys Ser Pro Ile Cys 1155 1160 1165 Glu Lys Gln Ala Leu Phe Ala LeuCys Lys Ser Val Lys Glu Asn Gly 1170 1175 1180 Leu Glu Pro His Leu ValLys Lys Val Leu Glu Lys Val Ser Glu Thr 1185 1190 1195 1200 Phe Gly TyrArg Arg Leu Glu Asp Phe Met Ala Ser His Leu Asp Tyr 1205 1210 1215 LeuVal Leu Glu Trp Leu Asn Leu Gln Asp Thr Glu Tyr Asn Leu Ser 1220 12251230 Ser Phe Pro Phe Ile Leu Leu Asn Tyr Thr Asn Ile Glu Asp Phe Tyr1235 1240 1245 Arg Ser Cys Tyr Lys Val Leu Ile Pro His Leu Val Ile ArgSer His 1250 1255 1260 Phe Asp Glu Val Lys Ser Ile Ala Asn Gln Ile GlnGlu Asp Trp Lys 1265 1270 1275 1280 Ser Leu Leu Thr Asp Cys Phe Pro LysIle Leu Val Asn Ile Leu Pro 1285 1290 1295 Tyr Phe Ala Tyr Glu Gly ThrArg Asp Ser Gly Met Ala Gln Gln Arg 1300 1305 1310 Glu Thr Ala Thr LysVal Tyr Asp Met Leu Lys Ser Glu Asn Leu Leu 1315 1320 1325 Gly Lys GlnIle Asp His Leu Phe Ile Ser Asn Leu Pro Glu Ile Val 1330 1335 1340 ValGlu Leu Leu Met Thr Leu His Glu Pro Ala Asn Ser Ser Ala Ser 1345 13501355 1360 Gln Ser Thr Asp Leu Cys Asp Phe Ser Gly Asp Leu Asp Pro AlaPro 1365 1370 1375 Asn Pro Pro His Phe Pro Ser His Val Ile Lys Ala ThrPhe Ala Tyr 1380 1385 1390 Ile Ser Asn Cys His Lys Thr Lys Leu Lys SerIle Leu Glu Ile Leu 1395 1400 1405 Ser Lys Ser Pro Asp Ser Tyr Gln LysIle Leu Leu Ala Ile Cys Glu 1410 1415 1420 Gln Ala Ala Glu Thr Asn AsnVal Tyr Lys Lys His Arg Ile Leu Lys 1425 1430 1435 1440 Ile Tyr His LeuPhe Val Ser Leu Leu Leu Lys Asp Ile Lys Ser Gly 1445 1450 1455 Leu GlyGly Ala Trp Ala Phe Val Leu Arg Asp Val Ile Tyr Thr Leu 1460 1465 1470Ile His Tyr Ile Asn Gln Arg Pro Ser Cys Ile Met Asp Val Ser Leu 14751480 1485 Arg Ser Phe Ser Leu Cys Cys Asp Leu Leu Ser Gln Val Cys GlnThr 1490 1495 1500 Ala Val Thr Tyr Cys Lys Asp Ala Leu Glu Asn His LeuHis Val Ile 1505 1510 1515 1520 Val Gly Thr Leu Ile Pro Leu Val Tyr GluGln Val Glu Val Gln Lys 1525 1530 1535 Gln Val Leu Asp Leu Leu Lys TyrLeu Val Ile Asp Asn Lys Asp Asn 1540 1545 1550 Glu Asn Leu Tyr Ile ThrIle Lys Leu Leu Asp Pro Phe Pro Asp His 1555 1560 1565 Val Val Phe LysAsp Leu Arg Ile Thr Gln Gln Lys Ile Lys Tyr Ser 1570 1575 1580 Arg GlyPro Phe Ser Leu Leu Glu Glu Ile Asn His Phe Leu Ser Val 1585 1590 15951600 Ser Val Tyr Asp Ala Leu Pro Leu Thr Arg Leu Glu Gly Leu Lys Asp1605 1610 1615 Leu Arg Arg Gln Leu Glu Leu His Lys Asp Gln Met Val AspIle Met 1620 1625 1630 Arg Ala Ser Gln Asp Asn Pro Gln Asp Gly Ile MetVal Lys Leu Val 1635 1640 1645 Val Asn Leu Leu Gln Leu Ser Lys Met AlaIle Asn His Thr Gly Glu 1650 1655 1660 Lys Glu Val Leu Glu Ala Val GlySer Cys Leu Gly Glu Val Gly Pro 1665 1670 1675 1680 Ile Asp Phe Ser ThrIle Ala Ile Gln His Ser Lys Asp Ala Ser Tyr 1685 1690 1695 Thr Lys AlaLeu Lys Leu Phe Glu Asp Lys Glu Leu Gln Trp Thr Phe 1700 1705 1710 IleMet Leu Thr Tyr Leu Asn Asn Thr Leu Val Glu Asp Cys Val Lys 1715 17201725 Val Arg Ser Ala Ala Val Thr Cys Leu Lys Asn Ile Leu Ala Thr Lys1730 1735 1740 Thr Gly His Ser Phe Trp Glu Ile Tyr Lys Met Thr Thr AspPro Met 1745 1750 1755 1760 Leu Ala Tyr Leu Gln Pro Phe Arg Thr Ser ArgLys Lys Phe Leu Glu 1765 1770 1775 Val Pro Arg Phe Asp Lys Glu Asn ProPhe Glu Gly Leu Asp Asp Ile 1780 1785 1790 Asn Leu Trp Ile Pro Leu SerGlu Asn His Asp Ile Trp Ile Lys Thr 1795 1800 1805 Leu Thr Cys Ala PheLeu Asp Ser Gly Gly Thr Lys Cys Glu Ile Leu 1810 1815 1820 Gln Leu LeuLys Pro Met Cys Glu Val Lys Thr Asp Phe Cys Gln Thr 1825 1830 1835 1840Val Leu Pro Tyr Leu Ile His Asp Ile Leu Leu Gln Asp Thr Asn Glu 18451850 1855 Ser Trp Arg Asn Leu Leu Ser Thr His Val Gln Gly Phe Phe ThrSer 1860 1865 1870 Cys Leu Arg His Phe Ser Gln Thr Ser Arg Ser Thr ThrPro Ala Asn 1875 1880 1885 Leu Asp Ser Glu Ser Glu His Phe Phe Arg CysCys Leu Asp Lys Lys 1890 1895 1900 Ser Gln Arg Thr Met Leu Ala Val ValAsp Tyr Met Arg Arg Gln Lys 1905 1910 1915 1920 Arg Pro Ser Ser Gly ThrIle Phe Asn Asp Ala Phe Trp Leu Asp Leu 1925 1930 1935 Asn Tyr Leu GluVal Ala Lys Val Ala Gln Ser Cys Ala Ala His Phe 1940 1945 1950 Thr AlaLeu Leu Tyr Ala Glu Ile Tyr Ala Asp Lys Lys Ser Met Asp 1955 1960 1965Asp Gln Glu Lys Arg Ser Leu Ala Phe Glu Glu Gly Ser Gln Ser Thr 19701975 1980 Thr Ile Ser Ser Leu Ser Glu Lys Ser Lys Glu Glu Thr Gly IleSer 1985 1990 1995 2000 Leu Gln Asp Leu Leu Leu Glu Ile Tyr Arg Ser IleGly Glu Pro Asp 2005 2010 2015 Ser Leu Tyr Gly Cys Gly Gly Gly Lys MetLeu Gln Pro Ile Thr Arg 2020 2025 2030 Leu Arg Thr Tyr Glu His Glu AlaMet Trp Gly Lys Ala Leu Val Thr 2035 2040 2045 Tyr Asp Leu Glu Thr AlaIle Pro Ser Ser Thr Arg Gln Ala Gly Ile 2050 2055 2060 Ile Gln Ala LeuGln Asn Leu Gly Leu Cys His Ile Leu Ser Val Tyr 2065 2070 2075 2080 LeuLys Gly Leu Asp Tyr Glu Asn Lys Asp Trp Cys Pro Glu Leu Glu 2085 20902095 Glu Leu His Tyr Gln Ala Ala Trp Arg Asn Met Gln Trp Asp His Cys2100 2105 2110 Thr Ser Val Ser Lys Glu Val Glu Gly Thr Ser Tyr His GluSer Leu 2115 2120 2125 Tyr Asn Ala Leu Gln Ser Leu Arg Asp Arg Glu PheSer Thr Phe Tyr 2130 2135 2140 Glu Ser Leu Lys Tyr Ala Arg Val Lys GluVal Glu Glu Met Cys Lys 2145 2150 2155 2160 Arg Ser Leu Glu Ser Val TyrSer Leu Tyr Pro Thr Leu Ser Arg Leu 2165 2170 2175 Gln Ala Ile Gly GluLeu Glu Ser Ile Gly Glu Leu Phe Ser Arg Ser 2180 2185 2190 Val Thr HisArg Gln Leu Ser Glu Val Tyr Ile Lys Trp Gln Lys His 2195 2200 2205 SerGln Leu Leu Lys Asp Ser Asp Phe Ser Phe Gln Glu Pro Ile Met 2210 22152220 Ala Leu Arg Thr Val Ile Leu Glu Ile Leu Met Glu Lys Glu Met Asp2225 2230 2235 2240 Asn Ser Gln Arg Glu Cys Ile Lys Asp Ile Leu Thr LysHis Leu Val 2245 2250 2255 Glu Leu Ser Ile Leu Ala Arg Thr Phe Lys AsnThr Gln Leu Pro Glu 2260 2265 2270 Arg Ala Ile Phe Gln Ile Lys Gln TyrAsn Ser Val Ser Cys Gly Val 2275 2280 2285 Ser Glu Trp Gln Leu Glu GluAla Gln Val Phe Trp Ala Lys Lys Glu 2290 2295 2300 Gln Ser Leu Ala LeuSer Ile Leu Lys Gln Met Ile Lys Lys Leu Asp 2305 2310 2315 2320 Ala SerCys Ala Ala Asn Asn Pro Ser Leu Lys Leu Thr Tyr Thr Glu 2325 2330 2335Cys Leu Arg Val Cys Gly Asn Trp Leu Ala Glu Thr Cys Leu Glu Asn 23402345 2350 Pro Ala Val Ile Met Gln Thr Tyr Leu Glu Lys Ala Val Glu ValAla 2355 2360 2365 Gly Asn Tyr Asp Gly Glu Ser Ser Asp Glu Leu Arg AsnGly Lys Met 2370 2375 2380 Lys Ala Phe Leu Ser Leu Ala Arg Phe Ser AspThr Gln Tyr Gln Arg 2385 2390 2395 2400 Ile Glu Asn Tyr Met Lys Ser SerGlu Phe Glu Asn Lys Gln Ala Leu 2405 2410 2415 Leu Lys Arg Ala Lys GluGlu Val Gly Leu Leu Arg Glu His Lys Ile 2420 2425 2430 Gln Thr Asn ArgTyr Thr Val Lys Val Gln Arg Glu Leu Glu Leu Asp 2435 2440 2445 Glu LeuAla Leu Arg Ala Leu Lys Glu Asp Arg Lys Arg Phe Leu Cys 2450 2455 2460Lys Ala Val Glu Asn Tyr Ile Asn Cys Leu Leu Ser Gly Glu Glu His 24652470 2475 2480 Asp Met Trp Val Phe Arg Leu Cys Ser Leu Trp Leu Glu AsnSer Gly 2485 2490 2495 Val Ser Glu Val Asn Gly Met Met Lys Arg Asp GlyMet Lys Ile Pro 2500 2505 2510 Thr Tyr Lys Phe Leu Pro Leu Met Tyr GlnLeu Ala Ala Arg Met Gly 2515 2520 2525 Thr Lys Met Met Gly Gly Leu GlyPhe His Glu Val Leu Asn Asn Leu 2530 2535 2540 Ile Ser Arg Ile Ser MetAsp His Pro His His Thr Leu Phe Ile Ile 2545 2550 2555 2560 Leu Ala LeuAla Asn Ala Asn Arg Asp Glu Phe Leu Thr Lys Pro Glu 2565 2570 2575 ValAla Arg Arg Ser Arg Ile Thr Lys Asn Val Pro Lys Gln Ser Ser 2580 25852590 Gln Leu Asp Glu Asp Arg Thr Glu Ala Ala Asn Arg Ile Ile Cys Thr2595 2600 2605 Ile Arg Ser Arg Arg Pro Gln Met Val Arg Ser Val Glu AlaLeu Cys 2610 2615 2620 Asp Ala Tyr Ile Ile Leu Ala Asn Leu Asp Ala ThrGln Trp Lys Thr 2625 2630 2635 2640 Gln Arg Lys Gly Ile Asn Ile Pro AlaAsp Gln Pro Ile Thr Lys Leu 2645 2650 2655 Lys Asn Leu Glu Asp Val ValVal Pro Thr Met Glu Ile Lys Val Asp 2660 2665 2670 His Thr Gly Glu TyrGly Asn Leu Val Thr Ile Gln Ser Phe Lys Ala 2675 2680 2685 Glu Phe ArgLeu Ala Gly Gly Val Asn Leu Pro Lys Ile Ile Asp Cys 2690 2695 2700 ValGly Ser Asp Gly Lys Glu Arg Arg Gln Leu Val Lys Gly Arg Asp 2705 27102715 2720 Asp Leu Arg Gln Asp Ala Val Met Gln Gln Val Phe Gln Met CysAsn 2725 2730 2735 Thr Leu Leu Gln Arg Asn Thr Glu Thr Arg Lys Arg LysLeu Thr Ile 2740 2745 2750 Cys Thr Tyr Lys Val Val Pro Leu Ser Gln ArgSer Gly Val Leu Glu 2755 2760 2765 Trp Cys Thr Gly Thr Val Pro Ile GlyGlu Phe Leu Val Asn Asn Glu 2770 2775 2780 Asp Gly Ala His Lys Arg TyrArg Pro Asn Asp Phe Ser Ala Phe Gln 2785 2790 2795 2800 Cys Gln Lys LysMet Met Glu Val Gln Lys Lys Ser Phe Glu Glu Lys 2805 2810 2815 Tyr GluVal Phe Met Asp Val Cys Gln Asn Phe Gln Pro Val Phe Arg 2820 2825 2830Tyr Phe Cys Met Glu Lys Phe Leu Asp Pro Ala Ile Trp Phe Glu Lys 28352840 2845 Arg Leu Ala Tyr Thr Arg Ser Val Ala Thr Ser Ser Ile Val GlyTyr 2850 2855 2860 Ile Leu Gly Leu Gly Asp Arg His Val Gln Asn Ile LeuIle Asn Glu 2865 2870 2875 2880 Gln Ser Ala Glu Leu Val His Ile Asp LeuGly Val Ala Phe Glu Gln 2885 2890 2895 Gly Lys Ile Leu Pro Thr Pro GluThr Val Pro Phe Arg Leu Thr Arg 2900 2905 2910 Asp Ile Val Asp Gly MetGly Ile Thr Gly Val Glu Gly Val Phe Arg 2915 2920 2925 Arg Cys Cys GluLys Thr Met Glu Val Met Arg Asn Ser Gln Glu Thr 2930 2935 2940 Leu LeuThr Ile Val Glu Val Leu Leu Tyr Asp Pro Leu Phe Asp Trp 2945 2950 29552960 Thr Met Asn Pro Leu Lys Ala Leu Tyr Leu Gln Gln Arg Pro Glu Asp2965 2970 2975 Glu Thr Glu Leu His Pro Thr Leu Asn Ala Asp Asp Gln GluCys Lys 2980 2985 2990 Arg Asn Leu Ser Asp Ile Asp Gln Ser Phe Asp LysVal Ala Glu Arg 2995 3000 3005 Val Leu Met Arg Leu Gln Glu Lys Leu LysGly Val Glu Glu Gly Thr 3010 3015 3020 Val Leu Ser Val Gly Gly Gln ValAsn Leu Leu Ile Gln Gln Ala Ile 3025 3030 3035 3040 Asp Pro Lys Asn LeuSer Arg Leu Phe Pro Gly Trp Lys Ala Trp Val 3045 3050 3055 21 450 PRTHomo sapiens 21 Met Ser Ala Ile Gln Ala Ala Trp Pro Ser Gly Thr Glu CysIle Ala 1 5 10 15 Lys Tyr Asn Phe His Gly Thr Ala Glu Gln Asp Leu ProPhe Cys Lys 20 25 30 Gly Asp Val Leu Thr Ile Val Ala Val Thr Lys Asp ProAsn Trp Tyr 35 40 45 Lys Ala Lys Asn Lys Val Gly Arg Glu Gly Ile Ile ProAla Asn Tyr 50 55 60 Val Gln Lys Arg Glu Gly Val Lys Ala Gly Thr Lys LeuSer Leu Met 65 70 75 80 Pro Trp Phe His Gly Lys Ile Thr Arg Glu Gln AlaGlu Arg Leu Leu 85 90 95 Tyr Pro Pro Glu Thr Gly Leu Phe Leu Val Arg GluSer Thr Asn Tyr 100 105 110 Pro Gly Asp Tyr Thr Leu Cys Val Ser Cys AspGly Lys Val Glu His 115 120 125 Tyr Arg Ile Met Tyr His Ala Ser Lys LeuSer Ile Asp Glu Glu Val 130 135 140 Tyr Phe Glu Asn Leu Met Gln Leu ValGlu His Tyr Thr Ser Asp Ala 145 150 155 160 Asp Gly Leu Cys Thr Arg LeuIle Lys Pro Lys Val Met Glu Gly Thr 165 170 175 Val Ala Ala Gln Asp GluPhe Tyr Arg Ser Gly Trp Ala Leu Asn Met 180 185 190 Lys Glu Leu Lys LeuLeu Gln Thr Ile Gly Lys Gly Glu Phe Gly Asp 195 200 205 Val Met Leu GlyAsp Tyr Arg Gly Asn Lys Val Ala Val Lys Cys Ile 210 215 220 Lys Asn AspAla Thr Ala Gln Ala Phe Leu Ala Glu Ala Ser Val Met 225 230 235 240 ThrGln Leu Arg His Ser Asn Leu Val Gln Leu Leu Gly Val Ile Val 245 250 255Glu Glu Lys Gly Gly Leu Tyr Ile Val Thr Glu Tyr Met Ala Lys Gly 260 265270 Ser Leu Val Asp Tyr Leu Arg Ser Arg Gly Arg Ser Val Leu Gly Gly 275280 285 Asp Cys Leu Leu Lys Phe Ser Leu Asp Val Cys Glu Ala Met Glu Tyr290 295 300 Leu Glu Gly Asn Asn Phe Val His Arg Asp Leu Ala Ala Arg AsnVal 305 310 315 320 Leu Val Ser Glu Asp Asn Val Ala Lys Val Ser Asp PheGly Leu Thr 325 330 335 Lys Glu Ala Ser Ser Thr Gln Asp Thr Gly Lys LeuPro Val Lys Trp 340 345 350 Thr Ala Pro Glu Ala Leu Arg Glu Lys Lys PheSer Thr Lys Ser Asp 355 360 365 Val Trp Ser Phe Gly Ile Leu Leu Trp GluIle Tyr Ser Phe Gly Arg 370 375 380 Val Pro Tyr Pro Arg Ile Pro Leu LysAsp Val Val Pro Arg Val Glu 385 390 395 400 Lys Gly Tyr Lys Met Asp AlaPro Asp Gly Cys Pro Pro Ala Val Tyr 405 410 415 Glu Val Met Lys Asn CysTrp His Leu Asp Ala Ala Met Arg Pro Ser 420 425 430 Phe Leu Gln Leu ArgGlu Gln Leu Glu His Ile Lys Thr His Glu Leu 435 440 445 His Leu 450 221142 PRT Homo sapiens 22 Met Ala Phe Cys Ala Lys Met Arg Ser Ser Lys LysThr Glu Val Asn 1 5 10 15 Leu Glu Ala Pro Glu Pro Gly Val Glu Val IlePhe Tyr Leu Ser Asp 20 25 30 Arg Glu Pro Leu Arg Leu Gly Ser Gly Glu TyrThr Ala Glu Glu Leu 35 40 45 Cys Ile Arg Ala Ala Gln Ala Cys Arg Ile SerPro Leu Cys His Asn 50 55 60 Leu Phe Ala Leu Tyr Asp Glu Asn Thr Lys LeuTrp Tyr Ala Pro Asn 65 70 75 80 Arg Thr Ile Thr Val Asp Asp Lys Met SerLeu Arg Leu His Tyr Arg 85 90 95 Met Arg Phe Tyr Phe Thr Asn Trp His GlyThr Asn Asp Asn Glu Gln 100 105 110 Ser Val Trp Arg His Ser Pro Lys LysGln Lys Asn Gly Tyr Glu Lys 115 120 125 Lys Lys Ile Pro Asp Ala Thr ProLeu Leu Asp Ala Ser Ser Leu Glu 130 135 140 Tyr Leu Phe Ala Gln Gly GlnTyr Asp Leu Val Lys Cys Leu Ala Pro 145 150 155 160 Ile Arg Asp Pro LysThr Glu Gln Asp Gly His Asp Ile Glu Asn Glu 165 170 175 Cys Leu Gly MetAla Val Leu Ala Ile Ser His Tyr Ala Met Met Lys 180 185 190 Lys Met GlnLeu Pro Glu Leu Pro Lys Asp Ile Ser Tyr Lys Arg Tyr 195 200 205 Ile ProGlu Thr Leu Asn Lys Ser Ile Arg Gln Arg Asn Leu Leu Thr 210 215 220 ArgMet Arg Ile Asn Asn Val Phe Lys Asp Phe Leu Lys Glu Phe Asn 225 230 235240 Asn Lys Thr Ile Cys Asp Ser Ser Val Ser Thr His Asp Leu Lys Val 245250 255 Lys Tyr Leu Ala Thr Leu Glu Thr Leu Thr Lys His Tyr Gly Ala Glu260 265 270 Ile Phe Glu Thr Ser Met Leu Leu Ile Ser Ser Glu Asn Glu MetAsn 275 280 285 Trp Phe His Ser Asn Asp Gly Gly Asn Val Leu Tyr Tyr GluVal Met 290 295 300 Val Thr Gly Asn Leu Gly Ile Gln Trp Arg His Lys ProAsn Val Val 305 310 315 320 Ser Val Glu Lys Glu Lys Asn Lys Leu Lys ArgLys Lys Leu Glu Asn 325 330 335 Lys Asp Lys Lys Asp Glu Glu Lys Asn LysIle Arg Glu Glu Trp Asn 340 345 350 Asn Phe Ser Phe Phe Pro Glu Ile ThrHis Ile Val Ile Lys Glu Ser 355 360 365 Val Val Ser Ile Asn Lys Gln AspAsn Lys Lys Met Glu Leu Lys Leu 370 375 380 Ser Ser His Glu Glu Ala LeuSer Phe Val Ser Leu Val Asp Gly Tyr 385 390 395 400 Phe Arg Leu Thr AlaAsp Ala His His Tyr Leu Cys Thr Asp Val Ala 405 410 415 Pro Pro Leu IleVal His Asn Ile Gln Asn Gly Cys His Gly Pro Ile 420 425 430 Cys Thr GluTyr Ala Ile Asn Lys Leu Arg Gln Glu Gly Ser Glu Glu 435 440 445 Gly MetTyr Val Leu Arg Trp Ser Cys Thr Asp Phe Asp Asn Ile Leu 450 455 460 MetThr Val Thr Cys Phe Glu Lys Ser Glu Gln Val Gln Gly Ala Gln 465 470 475480 Lys Gln Phe Lys Asn Phe Gln Ile Glu Val Gln Lys Gly Arg Tyr Ser 485490 495 Leu His Gly Ser Asp Arg Ser Phe Pro Ser Leu Gly Asp Leu Met Ser500 505 510 His Leu Lys Lys Gln Ile Leu Arg Thr Asp Asn Ile Ser Phe MetLeu 515 520 525 Lys Arg Cys Cys Gln Pro Lys Pro Arg Glu Ile Ser Asn LeuLeu Val 530 535 540 Ala Thr Lys Lys Ala Gln Glu Trp Gln Pro Val Tyr ProMet Ser Gln 545 550 555 560 Leu Ser Phe Asp Arg Ile Leu Lys Lys Asp LeuVal Gln Gly Glu His 565 570 575 Leu Gly Arg Gly Thr Arg Thr His Ile TyrSer Gly Thr Leu Met Asp 580 585 590 Tyr Lys Asp Asp Glu Gly Thr Ser GluGlu Lys Lys Ile Lys Val Ile 595 600 605 Leu Lys Val Leu Asp Pro Ser HisArg Asp Ile Ser Leu Ala Phe Phe 610 615 620 Glu Ala Ala Ser Met Met ArgGln Val Ser His Lys His Ile Val Tyr 625 630 635 640 Leu Tyr Gly Val CysVal Arg Asp Val Glu Asn Ile Met Val Glu Glu 645 650 655 Phe Val Glu GlyGly Pro Leu Asp Leu Phe Met His Arg Lys Ser Asp 660 665 670 Val Leu ThrThr Pro Trp Lys Phe Lys Val Ala Lys Gln Leu Ala Ser 675 680 685 Ala LeuSer Tyr Leu Glu Asp Lys Asp Leu Val His Gly Asn Val Cys 690 695 700 ThrLys Asn Leu Leu Leu Ala Arg Glu Gly Ile Asp Ser Glu Cys Gly 705 710 715720 Pro Phe Ile Lys Leu Ser Asp Pro Gly Ile Pro Ile Thr Val Leu Ser 725730 735 Arg Gln Glu Cys Ile Glu Arg Ile Pro Trp Ile Ala Pro Glu Cys Val740 745 750 Glu Asp Ser Lys Asn Leu Ser Val Ala Ala Asp Lys Trp Ser PheGly 755 760 765 Thr Thr Leu Trp Glu Ile Cys Tyr Asn Gly Glu Ile Pro LeuLys Asp 770 775 780 Lys Thr Leu Ile Glu Lys Glu Arg Phe Tyr Glu Ser ArgCys Arg Pro 785 790 795 800 Val Thr Pro Ser Cys Lys Glu Leu Ala Asp LeuMet Thr Arg Cys Met 805 810 815 Asn Tyr Asp Pro Asn Gln Arg Pro Phe PheArg Ala Ile Met Arg Asp 820 825 830 Ile Asn Lys Leu Glu Glu Gln Asn ProAsp Ile Val Ser Arg Lys Lys 835 840 845 Asn Gln Pro Thr Glu Val Asp ProThr His Phe Glu Lys Arg Phe Leu 850 855 860 Lys Arg Ile Arg Asp Leu GlyGlu Gly His Phe Gly Lys Val Glu Leu 865 870 875 880 Cys Arg Tyr Asp ProGlu Asp Asn Thr Gly Glu Gln Val Ala Val Lys 885 890 895 Ser Leu Lys ProGlu Ser Gly Gly Asn His Ile Ala Asp Leu Lys Lys 900 905 910 Glu Ile GluIle Leu Arg Asn Leu Tyr His Glu Asn Ile Val Lys Tyr 915 920 925 Lys GlyIle Cys Thr Glu Asp Gly Gly Asn Gly Ile Lys Leu Ile Met 930 935 940 GluPhe Leu Pro Ser Gly Ser Leu Lys Glu Tyr Leu Pro Lys Asn Lys 945 950 955960 Asn Lys Ile Asn Leu Lys Gln Gln Leu Lys Tyr Ala Val Gln Ile Cys 965970 975 Lys Gly Met Asp Tyr Leu Gly Ser Arg Gln Tyr Val His Arg Asp Leu980 985 990 Ala Ala Arg Asn Val Leu Val Glu Ser Glu His Gln Val Lys IleGly 995 1000 1005 Asp Phe Gly Leu Thr Lys Ala Ile Glu Thr Asp Lys GluTyr Tyr Thr 1010 1015 1020 Val Lys Asp Asp Arg Asp Ser Pro Val Phe TrpTyr Ala Pro Glu Cys 1025 1030 1035 1040 Leu Met Gln Ser Lys Phe Tyr IleAla Ser Asp Val Trp Ser Phe Gly 1045 1050 1055 Val Thr Leu His Glu LeuLeu Thr Tyr Cys Asp Ser Asp Ser Ser Pro 1060 1065 1070 Met Ala Leu PheLeu Lys Met Ile Gly Pro Thr His Gly Gln Met Thr 1075 1080 1085 Val ThrArg Leu Val Asn Thr Leu Lys Glu Gly Lys Arg Leu Pro Cys 1090 1095 1100Pro Pro Asn Cys Pro Asp Glu Val Tyr Gln Leu Met Arg Lys Cys Trp 11051110 1115 1120 Glu Phe Gln Pro Ser Asn Arg Thr Ser Phe Gln Asn Leu IleGlu Gly 1125 1130 1135 Phe Glu Ala Leu Leu Lys 1140 23 1338 PRT Homosapiens 23 Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu LeuSer 1 5 10 15 Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu LysAsp Pro 20 25 30 Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala GlyGln Thr 35 40 45 Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp SerLeu Pro 50 55 60 Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr LysSer Ala 65 70 75 80 Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser Thr Leu ThrLeu Asn Thr 85 90 95 Ala Gln Ala Asn His Thr Gly Phe Tyr Ser Cys Lys TyrLeu Ala Val 100 105 110 Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser Ala IleTyr Ile Phe Ile 115 120 125 Ser Asp Thr Gly Arg Pro Phe Val Glu Met TyrSer Glu Ile Pro Glu 130 135 140 Ile Ile His Met Thr Glu Gly Arg Glu LeuVal Ile Pro Cys Arg Val 145 150 155 160 Thr Ser Pro Asn Ile Thr Val ThrLeu Lys Lys Phe Pro Leu Asp Thr 165 170 175 Leu Ile Pro Asp Gly Lys ArgIle Ile Trp Asp Ser Arg Lys Gly Phe 180 185 190 Ile Ile Ser Asn Ala ThrTyr Lys Glu Ile Gly Leu Leu Thr Cys Glu 195 200 205 Ala Thr Val Asn GlyHis Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg 210 215 220 Gln Thr Asn ThrIle Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val 225 230 235 240 Lys LeuLeu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr 245 250 255 ProLeu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys 260 265 270Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His 275 280285 Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys 290295 300 Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys305 310 315 320 Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Phe IleThr Val 325 330 335 Lys His Arg Lys Gln Gln Val Leu Glu Thr Val Ala GlyLys Arg Ser 340 345 350 Tyr Arg Leu Ser Met Lys Val Lys Ala Phe Pro SerPro Glu Val Val 355 360 365 Trp Leu Lys Asp Gly Leu Pro Ala Thr Glu LysSer Ala Arg Tyr Leu 370 375 380 Thr Arg Gly Tyr Ser Leu Ile Ile Lys AspVal Thr Glu Glu Asp Ala 385 390 395 400 Gly Asn Tyr Thr Ile Leu Leu SerIle Lys Gln Ser Asn Val Phe Lys 405 410 415 Asn Leu Thr Ala Thr Leu IleVal Asn Val Lys Pro Gln Ile Tyr Glu 420 425 430 Lys Ala Val Ser Ser PhePro Asp Pro Ala Leu Tyr Pro Leu Gly Ser 435 440 445 Arg Gln Ile Leu ThrCys Thr Ala Tyr Gly Ile Pro Gln Pro Thr Ile 450 455 460 Lys Trp Phe TrpHis Pro Cys Asn His Asn His Ser Glu Ala Arg Cys 465 470 475 480 Asp PheCys Ser Asn Asn Glu Glu Ser Phe Ile Leu Asp Ala Asp Ser 485 490 495 AsnMet Gly Asn Arg Ile Glu Ser Ile Thr Gln Arg Met Ala Ile Ile 500 505 510Glu Gly Lys Asn Lys Met Ala Ser Thr Leu Val Val Ala Asp Ser Arg 515 520525 Ile Ser Gly Ile Tyr Ile Cys Ile Ala Ser Asn Lys Val Gly Thr Val 530535 540 Gly Arg Asn Ile Ser Phe Tyr Ile Thr Asp Val Pro Asn Gly Phe His545 550 555 560 Val Asn Leu Glu Lys Met Pro Thr Glu Gly Glu Asp Leu LysLeu Ser 565 570 575 Cys Thr Val Asn Lys Phe Leu Tyr Arg Asp Val Thr TrpIle Leu Leu 580 585 590 Arg Thr Val Asn Asn Arg Thr Met His Tyr Ser IleSer Lys Gln Lys 595 600 605 Met Ala Ile Thr Lys Glu His Ser Ile Thr LeuAsn Leu Thr Ile Met 610 615 620 Asn Val Ser Leu Gln Asp Ser Gly Thr TyrAla Cys Arg Ala Arg Asn 625 630 635 640 Val Tyr Thr Gly Glu Glu Ile LeuGln Lys Lys Glu Ile Thr Ile Arg 645 650 655 Asp Gln Glu Ala Pro Tyr LeuLeu Arg Asn Leu Ser Asp His Thr Val 660 665 670 Ala Ile Ser Ser Ser ThrThr Leu Asp Cys His Ala Asn Gly Val Pro 675 680 685 Glu Pro Gln Ile ThrTrp Phe Lys Asn Asn His Lys Ile Gln Gln Glu 690 695 700 Pro Gly Ile IleLeu Gly Pro Gly Ser Ser Thr Leu Phe Ile Glu Arg 705 710 715 720 Val ThrGlu Glu Asp Glu Gly Val Tyr His Cys Lys Ala Thr Asn Gln 725 730 735 LysGly Ser Val Glu Ser Ser Ala Tyr Leu Thr Val Gln Gly Thr Ser 740 745 750Asp Lys Ser Asn Leu Glu Leu Ile Thr Leu Thr Cys Thr Cys Val Ala 755 760765 Ala Thr Leu Phe Trp Leu Leu Leu Thr Leu Leu Ile Arg Lys Met Lys 770775 780 Arg Ser Ser Ser Glu Ile Lys Thr Asp Tyr Leu Ser Ile Ile Met Asp785 790 795 800 Pro Asp Glu Val Pro Leu Asp Glu Gln Cys Glu Arg Leu ProTyr Asp 805 810 815 Ala Ser Lys Trp Glu Phe Ala Arg Glu Arg Leu Lys LeuGly Lys Ser 820 825 830 Leu Gly Arg Gly Ala Phe Gly Lys Val Val Gln AlaSer Ala Phe Gly 835 840 845 Ile Lys Lys Ser Pro Thr Cys Arg Thr Val AlaVal Lys Met Leu Lys 850 855 860 Glu Gly Ala Thr Ala Ser Glu Tyr Lys AlaLeu Met Thr Glu Leu Lys 865 870 875 880 Ile Leu Thr His Ile Gly His HisLeu Asn Val Val Asn Leu Leu Gly 885 890 895 Ala Cys Thr Lys Gln Gly GlyPro Leu Met Val Ile Val Glu Tyr Cys 900 905 910 Lys Tyr Gly Asn Leu SerAsn Tyr Leu Lys Ser Lys Arg Asp Leu Phe 915 920 925 Phe Leu Asn Lys AspAla Ala Leu His Met Glu Pro Lys Lys Glu Lys 930 935 940 Met Glu Pro GlyLeu Glu Gln Gly Lys Lys Pro Arg Leu Asp Ser Val 945 950 955 960 Thr SerSer Glu Ser Phe Ala Ser Ser Gly Phe Gln Glu Asp Lys Ser 965 970 975 LeuSer Asp Val Glu Glu Glu Glu Asp Ser Asp Gly Phe Tyr Lys Glu 980 985 990Pro Ile Thr Met Glu Asp Leu Ile Ser Tyr Ser Phe Gln Val Ala Arg 995 10001005 Gly Met Glu Phe Leu Ser Ser Arg Lys Cys Ile His Arg Asp Leu Ala1010 1015 1020 Ala Arg Asn Ile Leu Leu Ser Glu Asn Asn Val Val Lys IleCys Asp 1025 1030 1035 1040 Phe Gly Leu Ala Arg Asp Ile Tyr Lys Asn ProAsp Tyr Val Arg Lys 1045 1050 1055 Gly Asp Thr Arg Leu Pro Leu Lys TrpMet Ala Pro Glu Ser Ile Phe 1060 1065 1070 Asp Lys Ile Tyr Ser Thr LysSer Asp Val Trp Ser Tyr Gly Val Leu 1075 1080 1085 Leu Trp Glu Ile PheSer Leu Gly Gly Ser Pro Tyr Pro Gly Val Gln 1090 1095 1100 Met Asp GluAsp Phe Cys Ser Arg Leu Arg Glu Gly Met Arg Met Arg 1105 1110 1115 1120Ala Pro Glu Tyr Ser Thr Pro Glu Ile Tyr Gln Ile Met Leu Asp Cys 11251130 1135 Trp His Arg Asp Pro Lys Glu Arg Pro Arg Phe Ala Glu Leu ValGlu 1140 1145 1150 Lys Leu Gly Asp Leu Leu Gln Ala Asn Val Gln Gln AspGly Lys Asp 1155 1160 1165 Tyr Ile Pro Ile Asn Ala Ile Leu Thr Gly AsnSer Gly Phe Thr Tyr 1170 1175 1180 Ser Thr Pro Ala Phe Ser Glu Asp PhePhe Lys Glu Ser Ile Ser Ala 1185 1190 1195 1200 Pro Lys Phe Asn Ser GlySer Ser Asp Asp Val Arg Tyr Val Asn Ala 1205 1210 1215 Phe Lys Phe MetSer Leu Glu Arg Ile Lys Thr Phe Glu Glu Leu Leu 1220 1225 1230 Pro AsnAla Thr Ser Met Phe Asp Asp Tyr Gln Gly Asp Ser Ser Thr 1235 1240 1245Leu Leu Ala Ser Pro Met Leu Lys Arg Phe Thr Trp Thr Asp Ser Lys 12501255 1260 Pro Lys Ala Ser Leu Lys Ile Asp Leu Arg Val Thr Ser Lys SerLys 1265 1270 1275 1280 Glu Ser Gly Leu Ser Asp Val Ser Arg Pro Ser PheCys His Ser Ser 1285 1290 1295 Cys Gly His Val Ser Glu Gly Lys Arg ArgPhe Thr Tyr Asp His Ala 1300 1305 1310 Glu Leu Glu Arg Lys Ile Ala CysCys Ser Pro Pro Pro Asp Tyr Asn 1315 1320 1325 Ser Val Val Leu Tyr SerThr Pro Pro Ile 1330 1335 24 309 PRT Homo sapiens 24 Met Asp Glu Lys ValPhe Thr Lys Glu Leu Asp Gln Trp Ile Glu Gln 1 5 10 15 Leu Asn Glu CysLys Gln Leu Ser Glu Ser Gln Val Lys Ser Leu Cys 20 25 30 Glu Lys Ala LysGlu Ile Leu Thr Lys Glu Ser Asn Val Gln Glu Val 35 40 45 Arg Cys Pro ValThr Val Cys Gly Asp Val His Gly Gln Phe His Asp 50 55 60 Leu Met Glu LeuPhe Arg Ile Gly Gly Lys Ser Pro Asp Thr Asn Tyr 65 70 75 80 Leu Phe MetGly Asp Tyr Val Asp Arg Gly Tyr Tyr Ser Val Glu Thr 85 90 95 Val Thr LeuLeu Val Ala Leu Lys Val Arg Tyr Arg Glu Arg Ile Thr 100 105 110 Ile LeuArg Gly Asn His Glu Ser Arg Gln Ile Thr Gln Val Tyr Gly 115 120 125 PheTyr Asp Glu Cys Leu Arg Lys Tyr Gly Asn Ala Asn Val Trp Lys 130 135 140Tyr Phe Thr Asp Leu Phe Asp Tyr Leu Pro Leu Thr Ala Leu Val Asp 145 150155 160 Gly Gln Ile Phe Cys Leu His Gly Gly Leu Ser Pro Ser Ile Asp Thr165 170 175 Leu Asp His Ile Arg Ala Leu Asp Arg Leu Gln Glu Val Pro HisGlu 180 185 190 Gly Pro Met Cys Asp Leu Leu Trp Ser Asp Pro Asp Asp ArgGly Gly 195 200 205 Trp Gly Ile Ser Pro Arg Gly Ala Gly Tyr Thr Phe GlyGln Asp Ile 210 215 220 Ser Glu Thr Phe Asn His Ala Asn Gly Leu Thr LeuVal Ser Arg Ala 225 230 235 240 His Gln Leu Val Met Glu Gly Tyr Asn TrpCys His Asp Arg Asn Val 245 250 255 Val Thr Ile Phe Ser Ala Pro Asn TyrCys Tyr Arg Cys Gly Asn Gln 260 265 270 Ala Ala Ile Met Glu Leu Asp AspThr Leu Lys Tyr Ser Phe Leu Gln 275 280 285 Phe Asp Pro Ala Pro Arg ArgGly Glu Pro His Val Thr Arg Arg Thr 290 295 300 Pro Asp Tyr Phe Leu 30525 394 PRT Homo sapiens 25 Met Val Thr Met Glu Glu Leu Arg Glu Met AspCys Ser Val Leu Lys 1 5 10 15 Arg Leu Met Asn Arg Asp Glu Asn Gly GlyGly Ala Gly Gly Ser Gly 20 25 30 Ser His Gly Thr Leu Gly Leu Pro Ser GlyGly Lys Cys Leu Leu Leu 35 40 45 Asp Cys Arg Pro Phe Leu Ala His Ser AlaGly Tyr Ile Leu Gly Ser 50 55 60 Val Asn Val Arg Cys Asn Thr Ile Val ArgArg Arg Ala Lys Gly Ser 65 70 75 80 Val Ser Leu Glu Gln Ile Leu Pro AlaGlu Glu Glu Val Arg Ala Arg 85 90 95 Leu Arg Ser Gly Leu Tyr Ser Ala ValIle Val Tyr Asp Glu Gly Ser 100 105 110 Pro Arg Ala Glu Ser Leu Arg GluAsp Ser Thr Val Ser Leu Val Val 115 120 125 Gln Ala Leu Arg Arg Asn AlaGlu Arg Thr Asp Ile Cys Leu Leu Lys 130 135 140 Gly Gly Tyr Glu Arg PheSer Ser Glu Tyr Pro Glu Phe Cys Ser Lys 145 150 155 160 Thr Lys Ala LeuAla Ala Ile Pro Pro Pro Val Pro Pro Ser Ala Thr 165 170 175 Glu Pro LeuAsp Leu Gly Cys Ser Ser Cys Gly Thr Pro Leu His Asp 180 185 190 Gln GlyGly Pro Val Glu Ile Leu Pro Phe Leu Tyr Leu Gly Ser Ala 195 200 205 TyrHis Ala Ala Arg Arg Asp Met Leu Asp Ala Leu Gly Ile Thr Ala 210 215 220Leu Leu Asn Val Ser Ser Asp Cys Pro Asn His Phe Glu Gly His Tyr 225 230235 240 Gln Tyr Lys Cys Ile Pro Val Glu Asp Asn His Lys Ala Asp Ile Ser245 250 255 Ser Trp Phe Met Glu Ala Ile Glu Tyr Ile Asp Ala Val Lys AspCys 260 265 270 Arg Gly Arg Val Leu Val His Cys Gln Ala Gly Ile Ser ArgSer Ala 275 280 285 Thr Ile Cys Leu Ala Tyr Leu Met Met Lys Lys Arg ValArg Leu Glu 290 295 300 Glu Ala Phe Glu Phe Val Lys Gln Arg Arg Ser IleIle Ser Pro Asn 305 310 315 320 Phe Ser Phe Met Gly Gln Leu Leu Gln PheGlu Ser Gln Val Leu Ala 325 330 335 Thr Ser Cys Ala Ala Glu Ala Ala SerPro Ser Gly Pro Leu Arg Glu 340 345 350 Arg Gly Lys Thr Pro Ala Thr ProThr Ser Gln Phe Val Phe Ser Phe 355 360 365 Pro Val Ser Val Gly Val HisSer Ala Pro Ser Ser Leu Pro Tyr Leu 370 375 380 His Ser Pro Ile Thr ThrSer Pro Ser Cys 385 390 26 185 PRT Homo sapiens 26 Met Ser Gly Ser PheGlu Leu Ser Val Gln Asp Leu Asn Asp Leu Leu 1 5 10 15 Ser Asp Gly SerGly Cys Tyr Ser Leu Pro Ser Gln Pro Cys Asn Glu 20 25 30 Val Thr Pro ArgIle Tyr Val Gly Asn Ala Ser Val Ala Gln Asp Ile 35 40 45 Pro Lys Leu GlnLys Leu Gly Ile Thr His Val Leu Asn Ala Ala Glu 50 55 60 Gly Arg Ser PheMet His Val Asn Thr Asn Ala Asn Phe Tyr Lys Asp 65 70 75 80 Ser Gly IleThr Tyr Leu Gly Ile Lys Ala Asn Asp Thr Gln Glu Phe 85 90 95 Asn Leu SerAla Tyr Phe Glu Arg Ala Ala Asp Phe Ile Asp Gln Ala 100 105 110 Leu AlaGln Lys Asn Gly Arg Val Leu Val His Cys Arg Glu Gly Tyr 115 120 125 SerArg Ser Pro Thr Leu Val Ile Ala Tyr Leu Met Met Arg Gln Lys 130 135 140Met Asp Val Lys Ser Ala Leu Ser Ile Val Arg Gln Asn Arg Glu Ile 145 150155 160 Gly Pro Asn Asp Gly Phe Leu Ala Gln Leu Cys Gln Leu Asn Asp Arg165 170 175 Leu Ala Lys Glu Gly Lys Leu Lys Pro 180 185 27 657 PRT Homosapiens 27 Met Arg Arg Ala Val Cys Phe Pro Ala Leu Cys Leu Leu Leu AsnLeu 1 5 10 15 His Ala Ala Gly Cys Phe Ser Gly Asn Asn Asp His Phe LeuAla Ile 20 25 30 Asn Gln Lys Lys Ser Gly Lys Pro Val Phe Ile Tyr Lys HisSer Gln 35 40 45 Asp Ile Glu Lys Ser Leu Asp Ile Ala Pro Gln Lys Ile TyrArg His 50 55 60 Ser Tyr His Ser Ser Ser Glu Ala Gln Val Ser Lys Arg HisGln Ile 65 70 75 80 Val Asn Ser Ala Phe Pro Arg Pro Ala Tyr Asp Pro SerLeu Asn Leu 85 90 95 Leu Ala Met Asp Gly Gln Asp Leu Glu Val Glu Asn LeuPro Ile Pro 100 105 110 Ala Ala Asn Val Ile Val Val Thr Leu Gln Met AspVal Asn Lys Leu 115 120 125 Asn Ile Thr Leu Leu Arg Ile Phe Arg Gln GlyVal Ala Ala Ala Leu 130 135 140 Gly Leu Leu Pro Gln Gln Val His Ile AsnArg Leu Ile Gly Lys Lys 145 150 155 160 Asn Ser Ile Glu Leu Phe Val SerPro Ile Asn Arg Lys Thr Gly Ile 165 170 175 Ser Asp Ala Leu Pro Ser GluGlu Val Leu Arg Ser Leu Asn Ile Asn 180 185 190 Val Leu His Gln Ser LeuSer Gln Phe Gly Ile Thr Glu Val Ser Pro 195 200 205 Glu Lys Asn Val LeuGln Gly Gln His Glu Ala Asp Lys Ile Trp Ser 210 215 220 Lys Glu Gly PheTyr Ala Val Val Ile Phe Leu Ser Ile Phe Val Ile 225 230 235 240 Ile ValThr Cys Leu Met Ile Leu Tyr Arg Leu Lys Glu Arg Phe Gln 245 250 255 LeuSer Leu Arg Gln Asp Lys Glu Lys Asn Gln Glu Ile His Leu Ser 260 265 270Pro Ile Thr Leu Gln Pro Ala Leu Ser Glu Ala Lys Thr Val His Ser 275 280285 Met Val Gln Pro Glu Gln Ala Pro Lys Val Leu Asn Val Val Val Asp 290295 300 Pro Gln Gly Arg Gly Ala Pro Glu Ile Arg Ala Thr Thr Ala Thr Ser305 310 315 320 Val Cys Pro Ser Pro Phe Lys Met Lys Pro Ile Gly Leu GlnGlu Arg 325 330 335 Arg Gly Ser Asn Val Ser Leu Thr Leu Asp Met Ser SerLeu Gly Asn 340 345 350 Ile Glu Pro Phe Val Ser Ile Pro Thr Pro Arg GluLys Val Ala Met 355 360 365 Glu Tyr Leu Gln Ser Ala Ser Arg Ile Leu ThrArg Ser Gln Leu Arg 370 375 380 Asp Val Val Ala Ser Ser His Leu Leu GlnSer Glu Phe Met Glu Ile 385 390 395 400 Pro Met Asn Phe Val Asp Pro LysGlu Ile Asp Ile Pro Arg His Gly 405 410 415 Thr Lys Asn Arg Tyr Lys ThrIle Leu Pro Asn Pro Leu Ser Arg Val 420 425 430 Cys Leu Arg Pro Lys AsnVal Thr Asp Ser Leu Ser Thr Tyr Ile Asn 435 440 445 Ala Asn Tyr Ile ArgGly Tyr Ser Gly Lys Glu Lys Ala Phe Ile Ala 450 455 460 Thr Gln Gly ProMet Ile Asn Thr Val Asp Asp Phe Trp Gln Met Val 465 470 475 480 Trp GlnGlu Asp Ser Pro Val Ile Val Met Ile Thr Lys Leu Lys Glu 485 490 495 LysAsn Glu Lys Cys Val Leu Tyr Trp Pro Glu Lys Arg Gly Ile Tyr 500 505 510Gly Lys Val Glu Val Leu Val Ile Ser Val Asn Glu Cys Asp Asn Tyr 515 520525 Thr Ile Arg Asn Leu Val Leu Lys Gln Gly Ser His Thr Gln His Val 530535 540 Lys His Tyr Trp Tyr Thr Ser Trp Pro Asp His Lys Thr Pro Asp Ser545 550 555 560 Ala Gln Pro Leu Leu Gln Leu Met Leu Asp Val Glu Glu AspArg Leu 565 570 575 Ala Ser Gln Gly Arg Gly Pro Val Val Val His Cys SerAla Gly Ile 580 585 590 Gly Arg Thr Gly Cys Phe Ile Ala Thr Ser Ile GlyCys Gln Gln Leu 595 600 605 Lys Glu Glu Gly Val Val Asp Ala Leu Ser IleVal Cys Gln Leu Arg 610 615 620 Met Asp Arg Gly Gly Met Val Gln Thr SerGlu Gln Tyr Glu Phe Val 625 630 635 640 His His Ala Leu Cys Leu Tyr GluSer Arg Leu Ser Ala Glu Thr Val 645 650 655 Gln 28 537 PRT Homo sapiens28 Glu Arg Leu Leu Gly Arg Pro Gln Pro Ile Val Met Glu Ala Leu Asp 1 510 15 Glu Ala Glu Gly Leu Gln Asp Ser Gln Arg Glu Met Pro Pro Pro Pro 2025 30 Pro Pro Ser Pro Pro Ser Asp Pro Ala Gln Lys Pro Pro Pro Arg Gly 3540 45 Ala Gly Ser His Ser Leu Thr Val Arg Ser Ser Leu Cys Leu Phe Ala 5055 60 Ala Ser Gln Phe Leu Leu Ala Cys Gly Val Leu Trp Phe Ser Gly Tyr 6570 75 80 Gly His Met Trp Ser Gln Asn Ala Thr Asn Leu Val Ser Ser Leu Leu85 90 95 Thr Leu Leu Lys Gln Leu Glu Pro Thr Ser Trp Leu Asp Ser Gly Thr100 105 110 Trp Gly Val Pro Gly Leu Leu Leu Val Phe Leu Ser Val Gly LeuVal 115 120 125 Leu Val Thr Thr Leu Val Trp His Leu Leu Arg Thr Pro ProGlu Pro 130 135 140 Pro Thr Pro Leu Pro Pro Glu Asp Arg Arg Gln Ser ValSer Arg Gln 145 150 155 160 Pro Ser Phe Thr Tyr Ser Glu Trp Met Glu GluLys Ile Glu Asp Asp 165 170 175 Phe Leu Asp Leu Asp Pro Val Pro Glu ThrPro Val Phe Asp Cys Val 180 185 190 Met Asp Ile Lys Pro Glu Ala Asp ProThr Ser Leu Thr Val Lys Ser 195 200 205 Met Gly Leu Gln Glu Arg Arg GlySer Asn Val Ser Leu Thr Leu Asp 210 215 220 Met Cys Thr Pro Gly Cys AsnGlu Glu Gly Phe Gly Tyr Leu Met Ser 225 230 235 240 Pro Arg Glu Glu SerAla Arg Glu Tyr Leu Leu Ser Ala Ser Arg Val 245 250 255 Leu Gln Ala GluGlu Leu His Glu Lys Ala Leu Asp Pro Phe Leu Leu 260 265 270 Gln Ala GluPhe Phe Glu Ile Pro Met Asn Phe Val Val Pro Lys Glu 275 280 285 Tyr AspIle Pro Gly Arg Cys Arg Lys Asn Arg Tyr Lys Thr Ile Leu 290 295 300 ProAsn Pro His Ser Arg Val Cys Leu Thr Ser Pro Asp Pro Asp Asp 305 310 315320 Pro Leu Ser Ser Tyr Ile Asn Ala Asn Tyr Ile Arg Gly Tyr Gly Gly 325330 335 Glu Glu Lys Val Tyr Ile Ala Thr Gln Gly Pro Ile Val Ser Thr Val340 345 350 Ala Asp Phe Trp Arg Met Val Trp Gln Glu His Thr Pro Ile IleVal 355 360 365 Met Ile Thr Asn Ile Glu Glu Met Asn Glu Lys Cys Thr GluTyr Trp 370 375 380 Pro Glu Glu Gln Val Ala Tyr Asp Gly Val Glu Ile ThrVal Gln Lys 385 390 395 400 Val Ile His Thr Glu Asp Tyr Arg Leu Arg LeuIle Ser Leu Lys Ser 405 410 415 Gly Thr Glu Glu Arg Gly Leu Lys His TyrTrp Phe Thr Ser Trp Pro 420 425 430 Asp Gln Lys Thr Pro Asp Arg Ala ProPro Leu Leu His Leu Val Arg 435 440 445 Glu Val Glu Glu Ala Ala Gln GlnGlu Gly Pro His Cys Ala Pro Ile 450 455 460 Ile Val His Cys Ser Ala GlyIle Gly Arg Thr Gly Cys Phe Ile Ala 465 470 475 480 Thr Ser Ile Cys CysGln Gln Leu Arg Gln Glu Gly Val Val Asp Ile 485 490 495 Leu Lys Thr ThrCys Gln Leu Arg Gln Asp Arg Gly Gly Met Ile Gln 500 505 510 His Cys GluGln Tyr Gln Phe Val His His Val Met Ser Leu Tyr Glu 515 520 525 Lys GlnLeu Ser His Gln Ser Pro Glu 530 535 29 403 PRT Homo sapiens 29 Met ThrAla Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg Arg Tyr 1 5 10 15 GlnGlu Asp Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro Asn Ile 20 25 30 IleAla Met Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr Arg Asn 35 40 45 AsnIle Asp Asp Val Val Arg Phe Leu Asp Ser Lys His Lys Asn His 50 55 60 TyrLys Ile Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr Ala Lys 65 70 75 80Phe Asn Cys Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn Pro Pro 85 90 95Gln Leu Glu Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln Trp Leu 100 105110 Ser Glu Asp Asp Asn His Val Ala Ala Ile His Cys Lys Ala Gly Lys 115120 125 Gly Arg Thr Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg Gly Lys130 135 140 Phe Leu Lys Ala Gln Glu Ala Leu Asp Phe Tyr Gly Glu Val ArgThr 145 150 155 160 Arg Asp Lys Lys Gly Val Thr Ile Pro Ser Gln Arg ArgTyr Val Tyr 165 170 175 Tyr Tyr Ser Tyr Leu Leu Lys Asn His Leu Asp TyrArg Pro Val Ala 180 185 190 Leu Leu Phe His Lys Met Met Phe Glu Thr IlePro Met Phe Ser Gly 195 200 205 Gly Thr Cys Asn Pro Gln Phe Val Val CysGln Leu Lys Val Lys Ile 210 215 220 Tyr Ser Ser Asn Ser Gly Pro Thr ArgArg Glu Asp Lys Phe Met Tyr 225 230 235 240 Phe Glu Phe Pro Gln Pro LeuPro Val Cys Gly Asp Ile Lys Val Glu 245 250 255 Phe Phe His Lys Gln AsnLys Met Leu Lys Lys Asp Lys Met Phe His 260 265 270 Phe Trp Val Asn ThrPhe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu 275 280 285 Lys Val Glu AsnGly Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys 290 295 300 Ser Ile GluArg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu 305 310 315 320 ThrLys Asn Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr 325 330 335Phe Ser Pro Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu 340 345350 Glu Pro Ser Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp 355360 365 Val Ser Asp Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp370 375 380 Ser Asp Pro Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr GlnIle 385 390 395 400 Thr Lys Val 30 447 PRT Homo sapiens 30 Met Arg SerSer Thr Leu Gln Asp Pro Arg Arg Arg Asp Pro Gln Asp 1 5 10 15 Asp ValTyr Val Asp Ile Thr Asp Arg Leu Arg Phe Ala Ile Leu Tyr 20 25 30 Ser ArgPro Lys Ser Ala Ser Asn Val His Tyr Phe Ser Ile Asp Asn 35 40 45 Glu LeuGlu Tyr Glu Asn Phe Ser Glu Asp Phe Gly Pro Leu Asn Leu 50 55 60 Ala MetVal Tyr Arg Tyr Cys Cys Lys Ile Asn Lys Lys Leu Lys Ser 65 70 75 80 IleThr Met Leu Arg Lys Lys Ile Val His Phe Thr Gly Ser Asp Gln 85 90 95 ArgLys Gln Ala Asn Ala Ala Phe Leu Val Gly Cys Tyr Met Val Ile 100 105 110Tyr Leu Gly Arg Thr Pro Glu Ala Ala Tyr Arg Ile Leu Ile Phe Gly 115 120125 Asp Thr Pro Tyr Ile Pro Phe Arg Asp Ala Ala Tyr Gly Ser Cys Asn 130135 140 Phe Tyr Ile Thr Leu Leu Asp Cys Phe His Ala Val Lys Lys Ala Met145 150 155 160 Gln Tyr Gly Phe Leu Asn Phe Asn Ser Phe Asn Leu Asp GluTyr Glu 165 170 175 His Tyr Glu Lys Ala Glu Asn Gly Asp Leu Asn Trp IleIle Pro Asp 180 185 190 Arg Phe Ile Ala Phe Cys Gly Pro His Ser Arg AlaArg Leu Glu Ser 195 200 205 Gly Tyr His Gln His Ser Pro Glu Thr Tyr IleGln Tyr Phe Lys Asn 210 215 220 His Asn Val Thr Thr Ile Ile Arg Leu AsnLys Arg Met Tyr Asp Ala 225 230 235 240 Lys Arg Phe Thr Asp Ala Gly PheAsp His His Asp Leu Phe Phe Ala 245 250 255 Asp Gly Ser Thr Pro Thr AspAla Ile Val Lys Arg Phe Leu Asp Ile 260 265 270 Cys Glu Asn Ala Glu GlyAla Ile Ala Val His Cys Lys Ala Gly Leu 275 280 285 Gly Arg Thr Gly ThrLeu Ile Ala Cys Tyr Ile Met Lys His Tyr Arg 290 295 300 Met Thr Ala AlaGlu Thr Ile Ala Trp Val Arg Ile Cys Arg Pro Gly 305 310 315 320 Leu ValIle Gly Pro Gln Gln Gln Phe Leu Val Met Lys Gln Thr Ser 325 330 335 LeuTrp Leu Glu Gly Asp Tyr Phe Arg Gln Arg Leu Lys Gly Gln Glu 340 345 350Asn Gly Gln His Arg Ala Ala Phe Ser Lys Leu Leu Ser Gly Val Asp 355 360365 Asp Ile Ser Ile Asn Gly Val Glu Asn Gln Asp Gln Gln Glu Pro Lys 370375 380 Pro Tyr Ser Asp Asp Asp Glu Ile Asn Gly Val Thr Gln Gly Asp Arg385 390 395 400 Ser Arg Ala Leu Lys Arg Arg Arg Gln Ser Lys Thr Asn AspIle Leu 405 410 415 Leu Pro Ser Pro Leu Ala Val Leu Thr Phe Thr Leu CysSer Val Val 420 425 430 Ile Trp Trp Ile Val Cys Asp Tyr Ile Leu Pro IleLeu Leu Phe 435 440 445 31 340 PRT Homo sapiens 31 Met Leu Glu Ala ProGly Pro Ser Asp Gly Cys Glu Leu Ser Asn Pro 1 5 10 15 Ser Ala Ser ArgVal Ser Cys Ala Gly Gln Met Leu Glu Val Gln Pro 20 25 30 Gly Leu Tyr PheGly Gly Ala Ala Ala Val Ala Glu Pro Asp His Leu 35 40 45 Arg Glu Ala GlyIle Thr Ala Val Leu Thr Val Asp Ser Glu Glu Pro 50 55 60 Ser Phe Lys AlaGly Pro Gly Val Glu Asp Leu Trp Arg Leu Phe Val 65 70 75 80 Pro Ala LeuAsp Lys Pro Glu Thr Asp Leu Leu Ser His Leu Asp Arg 85 90 95 Cys Val AlaPhe Ile Gly Gln Ala Arg Ala Glu Gly Arg Ala Val Leu 100 105 110 Val HisCys His Ala Gly Val Ser Arg Ser Val Ala Ile Ile Thr Ala 115 120 125 PheLeu Met Lys Thr Asp Gln Leu Pro Phe Glu Lys Ala Tyr Glu Lys 130 135 140Leu Gln Ile Leu Lys Pro Glu Ala Lys Met Asn Glu Gly Phe Glu Trp 145 150155 160 Gln Leu Lys Leu Tyr Gln Ala Met Gly Tyr Glu Val Asp Thr Ser Ser165 170 175 Ala Ile Tyr Lys Gln Tyr Arg Leu Gln Lys Val Thr Glu Lys TyrPro 180 185 190 Glu Leu Gln Asn Leu Pro Gln Glu Leu Phe Ala Val Asp ProThr Thr 195 200 205 Val Ser Gln Gly Leu Lys Asp Glu Val Leu Tyr Lys CysArg Lys Cys 210 215 220 Arg Arg Ser Leu Phe Arg Ser Ser Ser Ile Leu AspHis Arg Glu Gly 225 230 235 240 Ser Gly Pro Ile Ala Phe Ala His Lys ArgMet Thr Pro Ser Ser Met 245 250 255 Leu Thr Thr Gly Arg Gln Ala Gln CysThr Ser Tyr Phe Ile Glu Pro 260 265 270 Val Gln Trp Met Glu Ser Ala LeuLeu Gly Val Met Asp Gly Gln Leu 275 280 285 Leu Cys Pro Lys Cys Ser AlaLys Leu Gly Ser Phe Asn Trp Tyr Gly 290 295 300 Glu Gln Cys Ser Cys GlyArg Trp Ile Thr Pro Ala Phe Gln Ile His 305 310 315 320 Lys Asn Arg ValAsp Glu Met Lys Ile Leu Pro Val Leu Gly Ser Gln 325 330 335 Thr Gly LysIle 340 32 150 PRT Homo sapiens 32 Met Gly Val Gln Pro Pro Asn Phe SerTrp Val Leu Pro Gly Arg Leu 1 5 10 15 Ala Gly Leu Ala Leu Pro Arg LeuPro Ala His Tyr Gln Phe Leu Leu 20 25 30 Asp Leu Gly Val Arg His Leu ValSer Leu Thr Glu Arg Gly Pro Pro 35 40 45 His Ser Asp Ser Cys Pro Gly LeuThr Leu His Arg Leu Arg Ile Pro 50 55 60 Asp Phe Cys Pro Pro Ala Pro AspGln Ile Asp Arg Phe Val Gln Ile 65 70 75 80 Val Asp Glu Ala Asn Ala ArgGly Glu Ala Val Gly Val His Cys Ala 85 90 95 Leu Gly Phe Gly Arg Thr GlyThr Met Leu Ala Cys Tyr Leu Val Lys 100 105 110 Glu Arg Gly Leu Ala AlaGly Asp Ala Ile Ala Glu Ile Arg Arg Leu 115 120 125 Arg Pro Gly Pro IleGlu Thr Tyr Glu Gln Glu Lys Ala Val Phe Gln 130 135 140 Phe Tyr Gln ArgThr Lys 145 150 33 322 PRT Homo sapiens 33 Gly Leu Met Leu Arg Arg LeuArg Lys Gly Asn Leu Pro Ile Arg Ser 1 5 10 15 Ile Ile Pro Asn His AlaAsp Lys Glu Arg Phe Ala Thr Arg Cys Lys 20 25 30 Ala Ala Thr Val Leu LeuTyr Asp Glu Ala Thr Ala Glu Trp Gln Pro 35 40 45 Glu Pro Gly Ala Pro AlaSer Val Leu Gly Leu Leu Leu Gln Lys Leu 50 55 60 Arg Asp Asp Gly Cys GlnAla Tyr Tyr Leu Gln Gly Gly Phe Asn Lys 65 70 75 80 Phe Gln Thr Glu TyrSer Glu His Cys Glu Thr Asn Val Asp Ser Ser 85 90 95 Ser Ser Pro Ser SerSer Pro Pro Thr Ser Val Leu Gly Leu Gly Gly 100 105 110 Leu Arg Ile SerSer Asp Cys Ser Asp Gly Glu Ser Asp Arg Glu Leu 115 120 125 Pro Ser SerAla Thr Glu Ser Asp Gly Ser Pro Val Pro Ser Ser Gln 130 135 140 Pro AlaPhe Pro Val Gln Ile Leu Pro Tyr Leu Tyr Leu Gly Cys Ala 145 150 155 160Lys Asp Ser Thr Asn Leu Asp Val Leu Gly Lys Tyr Gly Ile Lys Tyr 165 170175 Ile Leu Asn Val Thr Pro Asn Leu Pro Asn Ala Phe Glu His Gly Gly 180185 190 Glu Phe Thr Tyr Lys Gln Ile Pro Ile Ser Asp His Trp Ser Gln Asn195 200 205 Leu Ser Gln Phe Phe Pro Glu Ala Ile Ser Phe Ile Asp Glu AlaArg 210 215 220 Ser Lys Lys Cys Gly Val Leu Val His Cys Leu Ala Gly IleSer Arg 225 230 235 240 Ser Val Thr Val Thr Val Ala Tyr Leu Met Gln LysMet Asn Leu Ser 245 250 255 Leu Asn Asp Ala Tyr Asp Phe Val Lys Arg LysLys Ser Asn Ile Ser 260 265 270 Pro Asn Phe Asn Phe Met Gly Gln Leu LeuAsp Phe Glu Arg Thr Leu 275 280 285 Gly Leu Ser Ser Pro Cys Asp Asn HisAla Ser Ser Glu Gln Leu Tyr 290 295 300 Phe Ser Thr Pro Thr Asn His AsnLeu Phe Pro Leu Asn Thr Leu Glu 305 310 315 320 Ser Thr 34 521 PRT Homosapiens 34 Met Ser Glu Pro Lys Ala Ile Asp Pro Lys Leu Ser Thr Thr AspArg 1 5 10 15 Val Val Lys Ala Val Pro Phe Pro Pro Ser His Arg Leu ThrAla Lys 20 25 30 Glu Val Phe Asp Asn Asp Gly Lys Pro Arg Val Asp Ile LeuLys Ala 35 40 45 His Leu Met Lys Glu Gly Arg Leu Glu Glu Ser Val Ala LeuArg Ile 50 55 60 Ile Thr Glu Gly Ala Ser Ile Leu Arg Gln Glu Lys Asn LeuLeu Asp 65 70 75 80 Ile Asp Ala Pro Val Thr Val Cys Gly Asp Ile His GlyGln Phe Phe 85 90 95 Asp Leu Met Lys Leu Phe Glu Val Gly Gly Ser Pro AlaAsn Thr Arg 100 105 110 Tyr Leu Phe Leu Gly Asp Tyr Val Asp Arg Gly TyrPhe Ser Ile Glu 115 120 125 Cys Val Leu Tyr Leu Trp Ala Leu Lys Ile LeuTyr Pro Lys Thr Leu 130 135 140 Phe Leu Leu Arg Gly Asn His Glu Cys ArgHis Leu Thr Glu Tyr Phe 145 150 155 160 Thr Phe Lys Gln Glu Cys Lys IleLys Tyr Ser Glu Arg Val Tyr Asp 165 170 175 Ala Cys Met Asp Ala Phe AspCys Leu Pro Leu Ala Ala Leu Met Asn 180 185 190 Gln Gln Phe Leu Cys ValHis Gly Gly Leu Ser Pro Glu Ile Asn Thr 195 200 205 Leu Asp Asp Ile ArgLys Leu Asp Arg Phe Lys Glu Pro Pro Ala Tyr 210 215 220 Gly Pro Met CysAsp Ile Leu Trp Ser Asp Pro Leu Glu Asp Phe Gly 225 230 235 240 Asn GluLys Thr Gln Glu His Phe Thr His Asn Thr Val Arg Gly Cys 245 250 255 SerTyr Phe Tyr Ser Tyr Pro Ala Val Cys Glu Phe Leu Gln His Asn 260 265 270Asn Leu Leu Ser Ile Leu Arg Ala His Glu Ala Gln Asp Ala Gly Tyr 275 280285 Arg Met Tyr Arg Lys Ser Gln Thr Thr Gly Phe Pro Ser Leu Ile Thr 290295 300 Ile Phe Ser Ala Pro Asn Tyr Leu Asp Val Tyr Asn Asn Lys Ala Ala305 310 315 320 Val Leu Lys Tyr Glu Asn Asn Val Met Asn Ile Arg Gln PheAsn Cys 325 330 335 Ser Pro His Pro Tyr Trp Leu Pro Asn Phe Met Asp ValPhe Thr Trp 340 345 350 Ser Leu Pro Phe Val Gly Glu Lys Val Thr Glu MetLeu Val Asn Val 355 360 365 Leu Asn Ile Cys Ser Asp Asp Glu Leu Gly SerGlu Glu Asp Gly Phe 370 375 380 Asp Gly Ala Thr Ala Ala Ala Arg Lys GluVal Ile Arg Asn Lys Ile 385 390 395 400 Arg Ala Ile Gly Lys Met Ala ArgVal Phe Ser Val Leu Arg Glu Glu 405 410 415 Ser Glu Ser Val Leu Thr LeuLys Gly Leu Thr Pro Thr Gly Met Leu 420 425 430 Pro Ser Gly Val Leu SerGly Gly Lys Gln Thr Leu Gln Ser Ala Thr 435 440 445 Val Glu Ala Ile GluAla Asp Glu Ala Ile Lys Gly Phe Ser Pro Gln 450 455 460 His Lys Ile ThrSer Phe Glu Glu Ala Lys Gly Leu Asp Arg Ile Asn 465 470 475 480 Glu ArgMet Pro Pro Arg Arg Asp Ala Met Pro Ser Asp Ala Asn Leu 485 490 495 AsnSer Ile Asn Lys Ala Leu Thr Ser Glu Thr Asn Gly Thr Asp Ser 500 505 510Asn Gly Ser Asn Ser Ser Asn Ile Gln 515 520 35 1267 PRT Homo sapiens 35Asp Leu Ser Arg Ser His Cys His Val Tyr Leu Ala His Leu Glu Asn 1 5 1015 Ser Phe Gly Pro Ser Gly Ala Arg Glu Gly Ser Leu Ser Ser Gln Asp 20 2530 Ser Arg Thr Glu Ser Ala Ser Leu Ser Gln Ser Gln Val Asn Gly Phe 35 4045 Phe Ala Ser His Leu Gly Asp Gln Thr Trp Gln Glu Ser Gln His Gly 50 5560 Ser Pro Ser Pro Ser Val Ile Ser Lys Ala Thr Glu Lys Glu Thr Phe 65 7075 80 Thr Asp Ser Asn Gln Ser Lys Thr Lys Lys Pro Gly Ile Ser Asp Val 8590 95 Thr Asp Tyr Ser Asp Arg Gly Asp Ser Asp Met Asp Glu Ala Thr Tyr100 105 110 Ser Ser Ser Gln Asp His Gln Thr Pro Lys Gln Glu Ser Ser SerSer 115 120 125 Val Asn Thr Ser Asn Lys Met Asn Phe Lys Thr Phe Pro SerSer Pro 130 135 140 Pro Arg Ser Gly Asp Ile Phe Glu Val Glu Leu Ala LysAsn Asp Asn 145 150 155 160 Ser Leu Gly Ile Ser Val Thr Gly Gly Val AsnThr Ser Val Arg His 165 170 175 Gly Gly Ile Tyr Val Lys Ala Val Ile ProGln Gly Ala Ala Glu Ser 180 185 190 Asp Gly Arg Ile His Lys Gly Asp ArgVal Leu Ala Val Asn Gly Val 195 200 205 Ser Leu Glu Gly Ala Thr His LysGln Ala Val Glu Thr Leu Arg Asn 210 215 220 Thr Gly Gln Val Val His LeuLeu Leu Glu Lys Gly Gln Ser Pro Thr 225 230 235 240 Ser Lys Glu His ValPro Val Thr Pro Gln Cys Thr Leu Ser Asp Gln 245 250 255 Asn Ala Gln GlyGln Gly Pro Glu Lys Val Lys Lys Thr Thr Gln Val 260 265 270 Lys Asp TyrSer Phe Val Thr Glu Glu Asn Thr Phe Glu Val Lys Leu 275 280 285 Phe LysAsn Ser Ser Gly Leu Gly Phe Ser Phe Ser Arg Glu Asp Asn 290 295 300 LeuIle Pro Glu Gln Ile Asn Ala Ser Ile Val Arg Val Lys Lys Leu 305 310 315320 Phe Pro Gly Gln Pro Ala Ala Glu Ser Gly Lys Ile Asp Val Gly Asp 325330 335 Val Ile Leu Lys Val Asn Gly Ala Ser Leu Lys Gly Leu Ser Gln Gln340 345 350 Glu Val Ile Ser Ala Leu Arg Gly Thr Ala Pro Glu Val Phe LeuLeu 355 360 365 Leu Cys Arg Pro Pro Pro Gly Val Leu Pro Glu Ile Asp ThrAla Leu 370 375 380 Leu Thr Pro Leu Gln Ser Pro Ala Gln Val Leu Pro AsnSer Ser Lys 385 390 395 400 Asp Ser Ser Gln Pro Ser Cys Val Glu Gln SerThr Ser Ser Asp Glu 405 410 415 Asn Glu Met Ser Asp Lys Ser Lys Lys GlnCys Lys Ser Pro Ser Arg 420 425 430 Lys Asp Ser Tyr Ser Asp Ser Ser GlySer Gly Glu Asp Asp Leu Val 435 440 445 Thr Ala Pro Ala Asn Ile Ser AsnSer Thr Trp Ser Ser Ala Leu His 450 455 460 Gln Thr Leu Ser Asn Met ValSer Gln Ala Gln Ser His His Glu Ala 465 470 475 480 Pro Arg Val Lys LysIle Pro Phe Val Pro Cys Phe Thr Ile Leu Arg 485 490 495 Lys Arg Pro AsnLys Pro Glu Phe Glu Asp Ser Asn Pro Ser Pro Leu 500 505 510 Pro Pro AspMet Ala Pro Gly Gln Ser Tyr Gln Pro Gln Ser Glu Ser 515 520 525 Ala SerSer Ser Ser Met Asp Lys Tyr His Ile His His Ile Ser Glu 530 535 540 ProThr Arg Gln Glu Asn Trp Thr Pro Leu Lys Asn Asp Leu Glu Asn 545 550 555560 His Leu Glu Asp Phe Glu Leu Glu Val Glu Leu Leu Ile Thr Leu Ile 565570 575 Lys Ser Glu Lys Gly Ser Leu Gly Phe Thr Val Thr Lys Gly Asn Gln580 585 590 Arg Ile Gly Cys Tyr Val His Asp Val Ile Gln Asp Pro Ala LysSer 595 600 605 Asp Gly Arg Leu Lys Pro Gly Asp Arg Leu Ile Lys Val AsnAsp Thr 610 615 620 Asp Val Thr Asn Met Thr His Thr Asp Ala Val Asn LeuLeu Arg Gly 625 630 635 640 Ser Lys Thr Val Arg Leu Val Ile Gly Arg ValLeu Glu Leu Pro Arg 645 650 655 Ile Pro Met Leu Pro His Leu Leu Pro AspIle Thr Leu Thr Cys Asn 660 665 670 Lys Glu Glu Leu Gly Phe Ser Leu CysGly Gly His Asp Ser Leu Tyr 675 680 685 Gln Val Val Tyr Ile Ser Asp IleAsn Pro Arg Ser Val Ala Ala Ile 690 695 700 Glu Gly Asn Leu Gln Leu LeuAsp Val Ile His Tyr Val Asn Gly Val 705 710 715 720 Ser Thr Gln Gly MetThr Leu Glu Glu Val Asn Arg Ala Leu Asp Met 725 730 735 Ser Leu Pro SerLeu Val Leu Lys Ala Thr Arg Asn Asp Leu Pro Val 740 745 750 Val Pro SerSer Lys Arg Ser Ala Val Ser Ala Pro Lys Ser Thr Lys 755 760 765 Gly AsnGly Ser Tyr Ser Val Gly Ser Cys Ser Gln Pro Ala Leu Thr 770 775 780 ProAsn Asp Ser Phe Ser Thr Val Ala Gly Glu Glu Ile Asn Glu Ile 785 790 795800 Ser Tyr Pro Lys Gly Lys Cys Ser Thr Tyr Gln Ile Lys Gly Ser Pro 805810 815 Asn Leu Thr Leu Pro Lys Glu Ser Tyr Ile Gln Glu Asp Asp Ile Tyr820 825 830 Asp Asp Ser Gln Glu Ala Glu Val Ile Gln Ser Leu Leu Asp ValVal 835 840 845 Asp Glu Glu Ser Gln Asn Leu Leu Asn Glu Asn Asn Ala AlaGly Tyr 850 855 860 Ser Cys Gly Pro Gly Thr Leu Lys Met Asn Gly Lys LeuSer Glu Glu 865 870 875 880 Arg Thr Glu Asp Thr Asp Cys Asp Gly Ser ProLeu Pro Glu Tyr Phe 885 890 895 Thr Glu Ala Thr Lys Met Asn Gly Cys GluGlu Tyr Cys Glu Glu Lys 900 905 910 Val Lys Ser Glu Ser Leu Ile Gln LysPro Gln Glu Lys Lys Thr Asp 915 920 925 Asp Asp Glu Ile Thr Trp Gly AsnAsp Glu Leu Pro Ile Glu Arg Thr 930 935 940 Asn His Glu Asp Ser Asp LysAsp His Ser Phe Leu Thr Asn Asp Glu 945 950 955 960 Leu Ala Val Leu ProVal Val Lys Val Leu Pro Ser Gly Lys Tyr Thr 965 970 975 Gly Ala Asn LeuLys Ser Val Ile Arg Val Leu Arg Val Ala Arg Ser 980 985 990 Gly Ile ProSer Lys Glu Leu Glu Asn Leu Gln Glu Leu Lys Pro Leu 995 1000 1005 AspGln Cys Leu Ile Gly Gln Thr Lys Glu Asn Arg Arg Lys Asn Arg 1010 10151020 Tyr Lys Asn Ile Leu Pro Tyr Asp Ala Thr Arg Val Pro Leu Gly Asp1025 1030 1035 1040 Glu Gly Gly Tyr Ile Asn Ala Ser Phe Ile Lys Ile ProVal Gly Lys 1045 1050 1055 Glu Glu Phe Val Tyr Ile Ala Cys Gln Gly ProLeu Pro Thr Thr Val 1060 1065 1070 Gly Asp Phe Trp Gln Met Ile Trp GluGln Lys Ser Thr Val Ile Ala 1075 1080 1085 Met Met Thr Gln Glu Val GluGly Glu Lys Ile Lys Cys Gln Arg Tyr 1090 1095 1100 Trp Pro Asn Ile LeuGly Lys Thr Thr Met Val Ser Asn Arg Leu Arg 1105 1110 1115 1120 Leu AlaLeu Val Arg Met Gln Gln Leu Lys Gly Phe Val Val Arg Ala 1125 1130 1135Met Thr Leu Glu Asp Ile Gln Thr Arg Glu Val Arg His Ile Ser His 11401145 1150 Leu Asn Phe Thr Ala Trp Pro Asp His Asp Thr Pro Ser Gln ProAsp 1155 1160 1165 Asp Leu Leu Thr Phe Ile Ser Tyr Met Arg His Ile HisArg Ser Gly 1170 1175 1180 Pro Ile Ile Thr His Cys Ser Ala Gly Ile GlyArg Ser Gly Thr Leu 1185 1190 1195 1200 Ile Cys Ile Asp Val Val Leu GlyLeu Ile Ser Gln Asp Leu Asp Phe 1205 1210 1215 Asp Ile Ser Asp Leu ValArg Cys Met Arg Leu Gln Arg His Gly Met 1220 1225 1230 Val Gln Thr GluAsp Gln Tyr Ile Phe Cys Tyr Gln Val Ile Leu Tyr 1235 1240 1245 Val LeuThr Arg Leu Gln Ala Glu Glu Glu Gln Lys Gln Gln Pro Gln 1250 1255 1260Leu Leu Lys 1265 36 551 PRT Homo sapiens 36 Met Asn Glu Ser Pro Asp ProThr Asp Leu Ala Gly Val Ile Ile Glu 1 5 10 15 Leu Gly Pro Asn Asp SerPro Gln Thr Ser Glu Phe Lys Gly Ala Thr 20 25 30 Glu Glu Ala Pro Ala LysGlu Ser Pro His Thr Ser Glu Phe Lys Gly 35 40 45 Ala Ala Arg Val Ser ProIle Ser Glu Ser Val Leu Ala Arg Leu Ser 50 55 60 Lys Phe Glu Val Glu AspAla Glu Asn Val Ala Ser Tyr Asp Ser Lys 65 70 75 80 Ile Lys Lys Ile ValHis Ser Ile Val Ser Ser Phe Ala Phe Gly Leu 85 90 95 Phe Gly Val Phe LeuVal Leu Leu Asp Val Thr Leu Ile Leu Ala Asp 100 105 110 Leu Ile Phe ThrAsp Ser Lys Leu Tyr Ile Pro Leu Glu Tyr Arg Ser 115 120 125 Ile Ser LeuAla Ile Ala Leu Phe Phe Leu Met Asp Val Leu Leu Arg 130 135 140 Val PheVal Glu Arg Arg Gln Gln Tyr Phe Ser Asp Leu Phe Asn Ile 145 150 155 160Leu Asp Thr Ala Ile Ile Val Ile Leu Leu Leu Val Asp Val Val Tyr 165 170175 Ile Phe Phe Asp Ile Lys Leu Leu Arg Asn Ile Pro Arg Trp Thr His 180185 190 Leu Leu Arg Leu Leu Arg Leu Ile Ile Leu Leu Arg Ile Phe His Leu195 200 205 Phe His Gln Lys Arg Gln Leu Glu Lys Leu Ile Arg Arg Arg ValSer 210 215 220 Glu Asn Lys Arg Arg Tyr Thr Arg Asp Gly Phe Asp Leu AspLeu Thr 225 230 235 240 Tyr Val Thr Glu Arg Ile Ile Ala Met Ser Phe ProSer Ser Gly Arg 245 250 255 Gln Ser Phe Tyr Arg Asn Pro Ile Lys Glu ValVal Arg Phe Leu Asp 260 265 270 Lys Lys His Arg Asn His Tyr Arg Val TyrAsn Leu Cys Ser Glu Arg 275 280 285 Ala Tyr Asp Pro Lys His Phe His AsnArg Val Val Arg Ile Met Ile 290 295 300 Asp Asp His Asn Val Pro Thr LeuHis Gln Met Val Val Phe Thr Lys 305 310 315 320 Glu Val Asn Glu Trp MetAla Gln Asp Leu Glu Asn Ile Val Ala Ile 325 330 335 His Cys Lys Gly GlyThr Asp Arg Thr Gly Thr Met Val Cys Ala Phe 340 345 350 Leu Ile Ala SerGlu Ile Cys Ser Thr Ala Lys Glu Ser Leu Tyr Tyr 355 360 365 Phe Gly GluArg Arg Thr Asp Lys Thr His Ser Glu Lys Phe Gln Gly 370 375 380 Val GluThr Pro Ser Gln Lys Arg Tyr Val Ala Tyr Phe Ala Gln Val 385 390 395 400Lys His Leu Tyr Asn Trp Asn Leu Pro Pro Arg Arg Ile Leu Phe Ile 405 410415 Lys His Phe Ile Ile Tyr Ser Ile Pro Arg Tyr Val Arg Asp Leu Lys 420425 430 Ile Gln Ile Glu Met Glu Lys Lys Val Val Phe Ser Thr Ile Ser Leu435 440 445 Gly Lys Cys Ser Val Leu Asp Asn Ile Thr Thr Asp Lys Ile LeuIle 450 455 460 Asp Val Phe Asp Gly Pro Pro Leu Tyr Asp Asp Val Lys ValGln Phe 465 470 475 480 Phe Tyr Ser Asn Leu Pro Thr Tyr Tyr Asp Asn CysSer Phe Tyr Phe 485 490 495 Trp Leu His Thr Ser Phe Ile Glu Asn Asn ArgLeu Tyr Leu Pro Lys 500 505 510 Asn Glu Leu Asp Asn Leu His Lys Gln LysAla Arg Arg Ile Tyr Pro 515 520 525 Ser Asp Phe Ala Val Glu Ile Leu PheGly Glu Lys Met Thr Ser Ser 530 535 540 Asp Val Val Ala Gly Ser Asp 545550 37 323 PRT Homo sapiens 37 Met Ala Asp Leu Asp Lys Leu Asn Ile AspSer Ile Ile Gln Arg Leu 1 5 10 15 Leu Glu Val Arg Gly Ser Lys Pro GlyLys Asn Val Gln Leu Gln Glu 20 25 30 Asn Glu Ile Arg Gly Leu Cys Leu LysSer Arg Glu Ile Phe Leu Ser 35 40 45 Gln Pro Ile Leu Leu Glu Leu Glu AlaPro Leu Lys Ile Cys Gly Asp 50 55 60 Ile His Gly Gln Tyr Tyr Asp Leu LeuArg Leu Phe Glu Tyr Gly Gly 65 70 75 80 Phe Pro Pro Glu Ser Asn Tyr LeuPhe Leu Gly Asp Tyr Val Asp Arg 85 90 95 Gly Lys Gln Ser Leu Glu Thr IleCys Leu Leu Leu Ala Tyr Lys Ile 100 105 110 Lys Tyr Pro Glu Asn Phe PheLeu Leu Arg Gly Asn His Glu Cys Ala 115 120 125 Ser Ile Asn Arg Ile TyrGly Phe Tyr Asp Glu Cys Lys Arg Arg Tyr 130 135 140 Asn Ile Lys Leu TrpLys Thr Phe Thr Asp Cys Phe Asn Cys Leu Pro 145 150 155 160 Ile Ala AlaIle Val Asp Glu Lys Ile Phe Cys Cys His Gly Gly Leu 165 170 175 Ser ProAsp Leu Gln Ser Met Glu Gln Ile Arg Arg Ile Met Arg Pro 180 185 190 ThrAsp Val Pro Asp Gln Gly Leu Leu Cys Asp Leu Leu Trp Ser Asp 195 200 205Pro Asp Lys Asp Val Leu Gly Trp Gly Glu Asn Asp Arg Gly Val Ser 210 215220 Phe Thr Phe Gly Ala Glu Val Val Ala Lys Phe Leu His Lys His Asp 225230 235 240 Leu Asp Leu Ile Cys Arg Ala His Gln Val Val Glu Asp Gly TyrGlu 245 250 255 Phe Phe Ala Lys Arg Gln Leu Val Thr Leu Phe Ser Ala ProAsn Tyr 260 265 270 Cys Gly Glu Phe Asp Asn Ala Gly Ala Met Met Ser ValAsp Glu Thr 275 280 285 Leu Met Cys Ser Phe Gln Ile Leu Lys Pro Ala GluLys Lys Lys Pro 290 295 300 Asn Ala Thr Arg Pro Val Thr Pro Pro Arg GlyMet Ile Thr Lys Gln 305 310 315 320 Ala Lys Lys 38 319 PRT Homo sapiens38 Asp Lys Leu Asn Ile Asp Ser Ile Ile Gln Arg Leu Leu Glu Val Arg 1 510 15 Gly Ser Lys Pro Gly Lys Asn Val Gln Leu Gln Glu Asn Glu Ile Arg 2025 30 Gly Leu Cys Leu Lys Ser Arg Glu Ile Phe Leu Ser Gln Pro Ile Leu 3540 45 Leu Glu Leu Glu Ala Pro Leu Lys Ile Cys Gly Asp Ile His Gly Gln 5055 60 Tyr Tyr Asp Leu Leu Arg Leu Phe Glu Tyr Gly Gly Phe Pro Pro Glu 6570 75 80 Ser Asn Tyr Leu Phe Leu Gly Asp Tyr Val Asp Arg Gly Lys Gln Ser85 90 95 Leu Glu Thr Ile Cys Leu Leu Leu Ala Tyr Lys Ile Lys Tyr Pro Glu100 105 110 Asn Phe Phe Leu Leu Arg Gly Asn His Glu Cys Ala Ser Ile AsnArg 115 120 125 Ile Tyr Gly Phe Tyr Asp Glu Cys Lys Arg Arg Tyr Asn IleLys Leu 130 135 140 Trp Lys Thr Phe Thr Asp Cys Phe Asn Cys Leu Pro IleAla Ala Ile 145 150 155 160 Val Asp Glu Lys Ile Phe Cys Cys His Gly GlyLeu Ser Pro Asp Leu 165 170 175 Gln Ser Met Glu Gln Ile Arg Arg Ile MetArg Pro Thr Asp Val Pro 180 185 190 Asp Gln Gly Leu Leu Cys Asp Leu LeuTrp Ser Asp Pro Asp Lys Asp 195 200 205 Val Leu Gly Trp Gly Glu Asn AspArg Gly Val Ser Phe Thr Phe Gly 210 215 220 Ala Glu Val Val Ala Lys PheLeu His Lys His Asp Leu Asp Leu Ile 225 230 235 240 Cys Arg Ala His GlnVal Val Glu Asp Gly Tyr Glu Phe Phe Ala Lys 245 250 255 Arg Gln Leu ValThr Leu Phe Ser Ala Pro Asn Tyr Cys Gly Glu Phe 260 265 270 Asp Asn AlaGly Ala Met Met Ser Val Asp Glu Thr Leu Met Cys Ser 275 280 285 Phe GlnIle Leu Lys Pro Ala Glu Lys Lys Lys Pro Asn Ala Thr Arg 290 295 300 ProVal Thr Pro Pro Arg Gly Met Ile Thr Lys Gln Ala Lys Lys 305 310 315 39309 PRT Homo sapiens 39 Met Asp Glu Lys Val Phe Thr Lys Glu Leu Asp GlnTrp Ile Glu Gln 1 5 10 15 Leu Asn Glu Cys Lys Gln Leu Ser Glu Ser GlnVal Lys Ser Leu Cys 20 25 30 Glu Lys Ala Lys Glu Ile Leu Thr Lys Glu SerAsn Val Gln Glu Val 35 40 45 Arg Cys Pro Val Thr Val Cys Gly Asp Val HisGly Gln Phe His Asp 50 55 60 Leu Met Glu Leu Phe Arg Ile Gly Gly Lys SerPro Asp Thr Asn Tyr 65 70 75 80 Leu Phe Met Gly Asp Tyr Val Asp Arg GlyTyr Tyr Ser Val Glu Thr 85 90 95 Val Thr Leu Leu Val Ala Leu Lys Val ArgTyr Arg Glu Arg Ile Thr 100 105 110 Ile Leu Arg Gly Asn His Glu Ser ArgGln Ile Thr Gln Val Tyr Gly 115 120 125 Phe Tyr Asp Glu Cys Leu Arg LysTyr Gly Asn Ala Asn Val Trp Lys 130 135 140 Tyr Phe Thr Asp Leu Phe AspTyr Leu Pro Leu Thr Ala Leu Val Asp 145 150 155 160 Gly Gln Ile Phe CysLeu His Gly Gly Leu Ser Pro Ser Ile Asp Thr 165 170 175 Leu Asp His IleArg Ala Leu Asp Arg Leu Gln Glu Val Pro His Glu 180 185 190 Gly Pro MetCys Asp Leu Leu Trp Ser Asp Pro Asp Asp Arg Gly Gly 195 200 205 Trp GlyIle Ser Pro Arg Gly Ala Gly Tyr Thr Phe Gly Gln Asp Ile 210 215 220 SerGlu Thr Phe Asn His Ala Asn Gly Leu Thr Leu Val Ser Arg Ala 225 230 235240 His Gln Leu Val Met Glu Gly Tyr Asn Trp Cys His Asp Arg Asn Val 245250 255 Val Thr Ile Phe Ser Ala Pro Asn Tyr Cys Tyr Arg Cys Gly Asn Gln260 265 270 Ala Ala Ile Met Glu Leu Asp Asp Thr Leu Lys Tyr Ser Phe LeuGln 275 280 285 Phe Asp Pro Ala Pro Arg Arg Gly Glu Pro His Val Thr ArgArg Thr 290 295 300 Pro Asp Tyr Phe Leu 305 40 20 DNA ArtificialSequence Artificially Synthesized Primer Sequence 40 tacggaagtgttacttctgc 20 41 20 DNA Artificial Sequence Artificially SynthesizedPrimer Sequence 41 tgtgggaggt tttttctcta 20 42 17 DNA ArtificialSequence Artificially Synthesized Primer Sequence 42 gttttcccag tcacgac17 43 17 DNA Artificial Sequence Artificially Synthesized PrimerSequence 43 caggaaacag ctatgac 17

What is claimed is:
 1. An isolated nucleic acid of any one of (a) to (d)below: (a) a nucleic acid encoding a protein comprising the amino acidsequence of SEQ ID NO:2 or 4, (b) a nucleic acid comprising a codingregion in the nucleotide sequence of SEQ ID NO:1 or 3, (c) a nucleicacid encoding a protein that comprises the amino acid sequence of SEQ IDNO:2 or 4, in which one or more amino acids are replaced, deleted,inserted and/or added and that is functionally equivalent to the proteincomprising the amino acid sequence of SEQ ID NO:2 or 4, and (d) anucleic acid that hybridizes under stringent conditions with the nucleicacid comprising the nucleotide sequence of SEQ ID NO: 1 or 3, and thatencodes a protein functionally equivalent to the protein comprising theamino acid sequence of SEQ ID NO:2 or
 4. 2. An isolated nucleic acidencoding the amino acid sequence of SEQ ID NO:2 or 4 or a fragmentthereof.
 3. A vector into which the nucleic acid of claim 1 is inserted.4. A vector into which the nucleic acid of claim 2 is inserted.
 5. Atransformant harboring the nucleic acid of claim
 1. 6. A transformantharboring the nucleic acid of claim
 2. 7. A transformant harboring thevector of claim
 3. 8. A transformant harboring the vector of claim
 4. 9.A substantially purified polypeptide encoded by the nucleic acid ofclaim
 1. 10. A substantially purified polypeptide encoded by the nucleicacid of claim
 2. 11. A method for producing a polypeptide, the methodcomprising the steps of culturing the transformant of claim 7 andrecovering a polypeptide expressed from the transformant or the culturesupernatant thereof.
 12. A method for producing a polypeptide, themethod comprising the steps of culturing the transformant of claim 8 andrecovering a polypeptide expressed from the transformant or the culturesupernatant thereof.
 13. An antibody against the polypeptide of claim 9.14. An antibody against the polypeptide of claim
 10. 15. Apolynucleotide that hybridizes with the nucleic acid comprising thenucleotide sequence of SEQ ID NO: 1 or 3 or the complementary strandthereof and that comprises at least 15 nucleotides.
 16. A method forscreening for a compound that binds to the polypeptide of claim 9, themethod comprising the steps of: (a) contacting a test sample with thepolypeptide or a partial peptide thereof, (b) detecting a bindingactivity of the test sample to the polypeptide or the partial peptidethereof, and (c) selecting a compound comprising the binding activity tothe polypeptide or the partial peptide thereof.
 17. A method forscreening for a compound that binds to the polypeptide of claim 10, themethod comprising the steps of: (a) contacting a test sample with thepolypeptide or a partial peptide thereof, (b) detecting a bindingactivity of the test sample to the polypeptide or the partial peptidethereof, and (c) selecting a compound comprising the binding activity tothe polypeptide or the partial peptide thereof.